TECHNICAL FIELD
[0001] The present invention is directed to substituted, deuterium-enriched
N-Aryl pyridinones, pharmaceutically acceptable salts and prodrugs thereof, the chemical
synthesis thereof, and use of such compounds for the treatment and/or management of
a disease, disorder, or condition.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0002] This application claims the benefit of
U.S. Provisional Patent Application Nos. 62/731,570, filed on September 14, 2018;
62/750,377, filed on October 25, 2018;
62/839,256, filed on April 26, 2019; and
62/884,984, filed on August 9, 2019; the entirety of each of which is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0003] Fibrosis is a common feature of most chronic diseases, and fibrotic disorders are
estimated to contribute to 45% of deaths in the United States (
Wynn, Nat Rev Immunol. 2004 Aug; 4(8): 583-594). In organs of epithelial origin, such as lung, liver, skin, and kidney, normal cells
and tissues are remodeled with scar tissue composed of collagen and other extracellular
matrix molecules, ultimately resulting in loss of organ function and finally organ
failure. Pulmonary fibrosis, renal fibrosis, and hepatic cirrhosis are among the more
common fibrotic diseases, which together represent a large unmet clinical need.
[0004] Idiopathic pulmonary fibrosis (IPF) has received much attention due to the severe
course of disease. Drug development efforts in IPF have provided insight translatable
to other fibrotic disorders and have led to the recognition of commonalities in fibrotic
disease of varying origins. For example, the TGF-β pathway is a known a central mediator
of the initiation and maintenance of fibrosis in many fibrotic diseases (
Friedman et al., Sci Transl Med. 2013 Jan 9;5(167):167sr1). In vitro mechanistic studies, preclinical animal studies, and solid evidence that
this pathway is up-regulated in human disease suggest targeting the TGFβ pathway as
treatment of fibrosis. A number of agents, including antibodies directed against TGF-beta
or other pathway molecules, such as αvβ6 integrin, are currently being developed and
assessed in clinical studies for the treatment of diseases such as advanced focal
segmental glomerular sclerosis, scleroderma and IPF. However, even though elevated
TGF-beta signaling is a critical component of fibrotic disease, the cytokine also
carries out important normal homeostatic activities, including immune regulation and
tumor suppression, and as a consequence, design of clinical studies must account for
and minimize the potential adverse effects of systemic inhibition of TGFβ activity.
[0005] Lymphedema is a chronic debilitating disease of fibrotic and inflammatory origin,
that in developed countries such as the United States occurs most often as a complication
of cancer treatment. In such cases, lymphedema occurs as a result of iatrogenic injury
to the lymphatic system, usually as a result of lymph node dissection or biopsy. Large
skin excisions and adjuvant therapy with radiation may also cause lymphedema. See,
e.g.,
Szuba et al., Cancer 95:2260-2267 (2002);
Tsai et al., Ann. Surg. Oncol. 16: 1959-72 (2009);
Purushotham et al., J. Clin. Oncol. 23: 4312-4321 (2005). According to estimates, as many as 1 in 3 patients who undergo lymph node dissection
later develop lymphedema. Conservative estimates suggest that as many as 50,000 new
patients are diagnosed annually. See, e.g.,
DiSipio et al., Lancet Oncol. 14:500-515 (2013);
Petrek et al., Cancer 83: 2776-2781 (1998). Because lymphedema is a life-long disease with no cure, the number of affected
individuals is increasing annually with current estimates ranging between 5-6 million
Americans (
Rockson et al., Ann. NY Acad. Sci. 1131: 147-154 (2008)), and over 200 million people worldwide. It is likely that this number will continue
to increase in the future since the development of lymphedema is nearly linearly related
with cancer survivorship, and because the prevalence of known risk factors for lymphedema,
such as obesity and radiation, is rising. See, e.g.,
Erickson et al., J. Natl. Cancer Inst. 93: 96-111 (2001).
[0006] Lymphedema is disfiguring and debilitating; patients have chronic swelling of the
affected extremity, a sense of heaviness, pain, discomfort, skin damage, fibrosis,
recurrent infections, limited mobility, and decreased quality of life. See, e.g.,
Hayes et al., Cancer 118:2237-2249 (2012Severe symptoms can limit self care. When lymphedema first develops, the skin displays
pitting or dimpling, and as the disease progresses, and skin thickening and fibrosis
occurs, the skin can have a leathery texture. This non-pitting edema indicates an
irreversible stage of lymphedema, in which the has a mossy or cobblestoned (hyperkeratotic)
appearance. Adipose deposition is a defining characteristic of late-stage lymphedema.
Skin in chronic lymphedema is highly susceptible to fissures and recurrent cellulitis.
Concurrent cutaneous ulcerations, bacterial and fungal infections, and impetigo, a
skin condition resulting in red sores, are also common. Lymphorrhea, an oozing of
lymphatic fluid, is also frequently observed. Over time, elephantiasis nostras verrucosa
can develop, leading to severe disfiguration of body parts. Cosmetic deformities resulting
from lymphedema are difficult to conceal, and psychosocial stigmatization and low
self-esteem, depression, anxiety, and negative body image are common among lymphedema
patients because of impaired mobility, difficulty fitting into clothing, and deformity
of limbs and genitalia.
[0007] Additionally, in patients with chronic lymphedema lasting greater than 10 years there
is a 10% risk of developing angiosarcoma, a highly aggressive malignant tumor with
a poor prognosis and a 5-year survival rate. Other cancers have been associated with
lymphedema as well.
[0008] Once lymphedema develops, it is usually progressive. Despite the fact that lymphedema
is common and highly morbid, there is currently no cure, and treatment is palliative
with a goal of preventing disease progression rather than restoration of lymphatic
function.
Beaulac et al., Arch. Surg. 137; 1253-1257 (2002). As a result, patients are required to wear tight, uncomfortable garments for the
rest of their lives, in an effort to prevent lymphatic fluid buildup in the affected
extremity, and to undergo intense and time consuming physical therapy treatments.
Koul et al., Int. J. Radiat. Oncol. Biol. Phys., 67:841-846 (2007). In addition, despite on-going chronic care, some patients still have severe progression
of their disease with increasing swelling and frequent infections in the lymphedematous
limb.
[0009] There are currently no approved drug therapies for the treatment of lymphedema. Furthermore,
at present, there is no known pharmacologic therapy that can halt progression or promote
resolution of lymphedema.
Cormier et al., Ann. Surg. Oncol. 19:642-651 (2012). In addition, there has been little progress toward the development of meaningful
treatments for lymphatic diseases. Accordingly, development of targeted treatments
for lymphedema is therefore an important goal and is an unmet biomedical need.
SUMMARY OF THE INVENTION
[0010] The compounds described herein are designed to target the underlying fibrosis and
inflammation found in fibrotic-mediated and/or collagen-mediated disorders. The compounds
described herein are designed to target the underlying fibrosis and inflammation found
in the lymphatic system to improve lymphatic function and decrease the symptoms of
lymphedema and other lymphatic system disorders, such as those described herein.
[0011] In one aspect, the invention relates to a method of treating, preventing, and/or
ameliorating a disease, disorder, or condition. The method includes administering
to a subject in need thereof an effective amount of deuterium-enriched pirfenidone.
The deuterium-enriched pirfenidone has the structure shown in Formula I:

or a pharmaceutically acceptable salt thereof. R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 are selected from hydrogen and deuterium. At least one of R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 is deuterium. When R
7, R
8, R
9, R
10, and R
11 are deuterium, then at least one of R
1, R
2, R
3, R
4, R
5, and R
6 is deuterium.
[0012] In some embodiments, at least one of R
1, R
2, and R
3 is deuterium. In some embodiments, at least one of R
1, R
2, and R
3 independently has deuterium enrichment of no less than about 90%. In some embodiments,
R
1, R
2, and R
3 are deuterium.
[0013] The deuterium-enriched pirfenidone can have the following structure:

or a pharmaceutically acceptable salt thereof.
[0014] In some embodiments, the disease, disorder, or condition is selected from an inflammation-mediated
disorder, a fibrotic-meditated disorder, a collagen-mediated disorder, and a fibrotic-mediated
and collagen-mediated disorder or a combination of any of these disorders. In some
embodiments, the disease, disorder, or condition is selected from idiopathic pulmonary
fibrosis, pneumoconiosis, silicosis, chalicosis, asbestosis, anthracosis, lymphedema
(primary and/or secondary), systemic sclerosis (scleroderma) or a condition associated
with scleroderma, scleroderma interstitial lung disease, focal segmental glomerulosclerosis,
juvenile systemic sclerosis (J-SSC), diabetic nephropathy, lupus nephritis, polycystic
kidney disease, ANCA vasculitis, membranous nephropathy, minimal change disease, chronic
kidney disease, myocardial fibrosis, keloid scar, dermatopolymyositis, fibrotic sarcoidosis,
graft-versus-host disease, medical device or implant rejection, fatty liver disease,
non-alcoholic steatohepatitis (NASH), and hepatitis-C fibrosis. In some embodiments,
the disease, disorder, or condition is selected from neurofibromatosis, Hermansky-Pudlak
syndrome, diabetic nephropathy, renal fibrosis, hypertrophic cardiomyopathy (HCM),
hypertension-related nephropathy, glomerulosclerosis (FSGS), radiation-induced fibrosis,
multiple sclerosis (including secondary progressive multiple sclerosis), uterine leiomyomas
(fibroids), alcoholic liver disease selected from hepatic steatosis, hepatic fibrosis,
and hepatic cirrhosis, a proliferative disorder selected from an angiogenesis-mediated
disorder, a cancer selected from glioma, glioblastoma, breast cancer, colon cancer,
melanoma and pancreatic cancer, a fibrotic disorder, an interstitial lung disease,
atrial fibrillation (AF), organ transplant rejection, scleroderma and related fibrotic
conditions of the skin, endotoxin-induced liver injury after partial hepatectomy or
hepatic ischemia, allograft injury after organ transplantation, cystic fibrosis, atrial
fibrilation, neutropenia, dermatomyositis, cirrhosis, diffuse parenchymal lung disease,
mediastinal fibrosis, tuberculosis, spleen fibrosis caused by sickle-cell anemia,
rheumatoid arthritis, systemic sclerosis-related pulmonary fibrosis, sarcoidosis,
sarcoidosis-related pulmonary fibrosis, pulmonary fibrosis caused by infection, asbestos-induced
pulmonary fibrosis, silica-induced pulmonary fibrosis, environmentally induced pulmonary
fibrosis, radiation-induced pulmonary fibrosis, lupus-induced pulmonary fibrosis,
drug-induced pulmonary fibrosis, and hypersensitivity pneumonitis, and/or any disorder
ameliorated by modulating fibrosis and/or collagen infiltration into tissues.
[0015] In some embodiments, the disease, disorder, or condition is selected from idiopathic
pulmonary fibrosis, edema (primary and/or secondary), lymphedema (primary and/or secondary),
and systemic sclerosis (scleroderma) or a condition associated with scleroderma. In
some embodiments, the disease, disorder, or condition is scleroderma and at least
one related condition selected from interstitial lung disease, tightening of the skin,
joint pain, exaggerated response to cold (Raynaud's disease), and heartburn. In some
embodiments, the disease, disorder, or condition is selected from non-alcoholic steatohepatitis
(NASH), a fatty liver disease, or Hepatitis-C fibrosis.
[0016] The deuterium-enriched pirfenidone can have the structure shown in
Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the deuterium-enriched
pirfenidone has the structure shown in
Formula I and is administered orally. In some embodiments, the deuterium-enriched pirfenidone
has the structure shown in
Formula I and is administered locally. In some embodiments, the deuterium-enriched pirfenidone
has the structure shown in
Formula I and is administered orally intravenously.
[0017] In some embodiments, the deuterium-enriched pirfenidone has the structure shown as
LYT-100:

or a pharmaceutically acceptable salt thereof.
[0018] In some embodiments, the deuterium-enriched pirfenidone having the following structure:

or a pharmaceutically acceptable salt thereof is administered orally.
[0019] In some embodiments, the deuterium-enriched pirfenidone having the following structure:

or a pharmaceutically acceptable salt thereof is administered intravenously.
[0020] In some embodiments, the deuterium-enriched pirfenidone having the following structure:

or a pharmaceutically acceptable salt thereof is administered locally.
[0021] In some embodiments, the deuterium-enriched pirfenidone having the following structure:

or a pharmaceutically acceptable salt thereof is administered twice daily.
[0022] In some embodiments, the deuterium-enriched pirfenidone having the following structure:

or a pharmaceutically acceptable salt thereof is administered once daily.
[0023] In some embodiments, the deuterium-enriched pirfenidone having the following structure:

or a pharmaceutically acceptable salt thereof is administered three times daily.
[0024] In another aspect, the invention features a method of reducing inflammation and/or
fibrosis in a subject having insufficient lymphatic flow. The method includes administering
to a subject in need thereof an effective amount of deuterium-enriched pirfenidone
having the structure shown in Formula
I:

or a pharmaceutically acceptable salt thereof. R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 are selected from hydrogen and deuterium. At least one of R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 is deuterium. When R
7, R
8, R
9, R
10, and R
11 are deuterium, then at least one of R
1, R
2, R
3, R
4, R
5, and R
6 is deuterium.
[0025] In some embodiments, at least one of R
1, R
2, and R
3 is deuterium. In some embodiments, at least one of R
1, R
2, and R
3 independently has deuterium enrichment of no less than about 90%. In some embodiments,
R
1, R
2, and R
3 are deuterium.
[0026] The deuterium-enriched pirfenidone can have the following structure:

or a pharmaceutically acceptable salt thereof.
[0027] In another aspect, the invention features a method of modulating and/or maintaining
interstitial fluid balance and/or lymphatic flow in a subject in need thereof. The
method includes administering to the subject an effective amount of deuterium-enriched
pirfenidone having the structure shown in Formula
I:

or a pharmaceutically acceptable salt thereof. R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 are selected from hydrogen and deuterium. At least one of R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 is deuterium. When R
7, R
8, R
9, R
10, and R
11 are deuterium, then at least one of R
1, R
2, R
3, R
4, R
5, and R
6 is deuterium.
[0028] In some embodiments, at least one of R
1, R
2, and R
3 is deuterium. In some embodiments, at least one of R
1, R
2, and R
3 independently has deuterium enrichment of no less than about 90%. In some embodiments,
R
1, R
2, and R
3 are deuterium.
[0029] In some embodiments, the deuterium-enriched pirfenidone has the following structure:

or a pharmaceutically acceptable salt thereof.
[0030] In another aspect, the invention relates to a method of treating edema. The method
includes administering to a subject in need thereof an effective amount of deuterium-enriched
pirfenidone having the structure:

or a pharmaceutically acceptable salt thereof. R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 are selected from hydrogen and deuterium. At least one of R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 is deuterium. When R
7, R
8, R
9, R
10, and R
11 are deuterium, then at least one of R
1, R
2, R
3, R
4, R
5, and R
6 is deuterium. In some embodiments, the deuterium-enriched pirfenidone has the structure:

or a pharmaceutically acceptable salt thereof.
[0031] In some embodiments, the edema is lymphedema. In some embodiments, the lymphedema
is secondary lymphedema. In some embodiments, the lymphedema is primary lymphedema.
[0032] In some embodiments, progression of the disease or condition, e.g., edema, is halted
in the subject. In some embodiments, there is a stage reduction in the subject. In
some embodiments, treating includes decreasing swelling, decreasing inflammation,
decreasing fibrosis, decreasing pain, increasing range of motion, decreasing heaviness,
decreasing tightness, decreasing skin thickening, and/or improving lymphatic function.
In some embodiments, treating includes an improvement in the condition, e.g., edema,
as measured by water content, limb volume, tissue firmness, Visual-Analog Scale (VAS)
score, Upper Limb Lymphedema score (ULL27), Lymphedema Life Impact Scale (LLIS) score,
Functional Assessment of Cancer Therapy breast cancer-specific quality of life tool
score (FACT-B +4), lymphedema quality of life score (LYMQOL), Disabilities of the
Arm, Shoulder, and Hand score (DASH), and/or Lymphedema Quality of Life Inventory
(LQOLI).
[0033] The improvement in water content in a subject with edema is a reduction in water
content. Thus, in some embodiments, the water content in a limb of a subject with
edema is reduced. In some embodiments, the water content in a limb of a subject with
edema is reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 60%, 70%, 80%, 90% or more. In some embodiments, the water content
in a limb of a subject with edema, for example as measured by bioelectrical impedance
spectroscopy (BIS), is reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%,
20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, the water content
in a limb of a subject with edema, for example as measured by Tissue Dielectric Constant
(TDC), is reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%,
30%, 35%, 40%, 45%, 50%, or more. In some embodiments, limb volume is stabilized or
decreased in a subject with edema by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more. In some embodiments,
limb volume is stabilized or decreased by at least 2%. In some embodiments, tissue
firmness in a subject with edema improves by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%,
9%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90% or more. In some embodiments,
tissue firmness, as measured by tonometry, improves by 2%, 3%, 4%, 5%, 6%, 7%, 8%,
9%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, tissue firmness,
for example as measured by tonometry, improves by at least 20%.
[0034] In some embodiments, at least one of the positions represented as D independently
has deuterium enrichment of no less than about 95%. In some embodiments, at least
one of the positions represented as D independently has deuterium enrichment of no
less than about 98%. In some embodiments, at least one of the positions represented
as D independently has deuterium enrichment of no less than about 99%.
[0035] In some embodiments, an effective amount of deuterium-enriched pirfenidone is maintained
at a site of lymphedema in the subject.
[0036] In some embodiments, the subject has received treatment for cancer, and the lymphedema
is associated with the cancer treatment or diagnosis. In some embodiments, the subject
has breast cancer-related arm lymphedema. In some embodiments, the subject has mild
to moderate breast cancer-related lymphedema. In some embodiments, the subject is
receiving or may have received chemotherapy or radiation therapy.
[0037] In some embodiments, the deuterium-enriched pirfenidone is administered topically
twice a day. In some embodiments, the deuterium-enriched pirfenidone is administered
topically once a day. In some embodiments, the deuterium-enriched pirfenidone is administered
topically three times a day.
[0038] In another aspect, the invention features a method of treating interstitial lung
disease (ILD). The method includes administering to a subject in need thereof an effective
amount of deuterium-enriched pirfenidone having the structure:

or a pharmaceutically acceptable salt thereof. R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 are selected from hydrogen and deuterium. At least one of R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 is deuterium. When R
7, R
8, R
9, R
10, and R
11 are deuterium, then at least one of R
1, R
2, R
3, R
4, R
5, and R
6 is deuterium. The ILD is treated in the subject.
[0039] In some embodiments, the deuterium-enriched pirfenidone has the structure:

or a pharmaceutically acceptable salt thereof.
[0040] In some embodiments, the ILD is idiopathic pulmonary fibrosis (IPF). The deuterium-enriched
pirfenidone can be administered orally twice a day, for a total daily dose of 1000
mg. In some embodiments, the initial dosage is titrated from 250 mg to 1000 mg over
2 weeks.
[0041] In some embodiments, the subject experiences at least a 5% or 10% reduction in percent
predicted forced vital capacity (%FVC).
[0042] In another aspect, the invention features a method of treating a fibrotic or collagen
infiltration disorder. The method includes administering to a subject in need thereof
an effective amount of deuterium-enriched pirfenidone having the structure:

or a pharmaceutically acceptable salt thereof. R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 are selected from hydrogen and deuterium. At least one of R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 is deuterium. When R
7, R
8, R
9, R
10, and R
11 are deuterium, then at least one of R
1, R
2, R
3, R
4, R
5, and R
6 is deuterium. The fibrotic or collagen infiltration disorder is treated in the subject.
[0043] In some embodiments, the deuterium-enriched pirfenidone has the structure:

or a pharmaceutically acceptable salt thereof.
[0044] In another aspect, the methods include measuring or monitoring a biomarker, e.g.,
a marker of inflammation, in a subject. In some embodiments, the marker is one or
more markers selected from G-CSF, MIG, FGF-2, IL-4, IL-10, lymphotoxin-α/TNF-β, leptin,
IL-6, IL-1β, TNF-α, TGF-β1, MMP-9, TIMP-1, and MCP-1. In some embodiments, a biomarker
is monitored to monitor the treatment of the subject.
BRIEF DESCRIPTION OF THE FIGURES
[0045]
FIG. 1A illustrates the single-dose pharmacokinetics of an 801 mg dose of LYT-100 and 801
mg dose of pirfenidone over 24 hours. FIG. 1B illustrates an individual's single dose pharmacokinetics of an 801mg dose of LYT-100
and 801 mg dose of pirfenidone over 48 hours. FIG. 1C is a model of a 500 mg twice daily dose of LYT-100 (total daily dose of 1000 mg)
and its metabolites on day 7. FIG. 1D is a model of a 750 mg twice daily dose of LYT-100 (total daily dose of 1500 mg)
and its metabolites on day 7. FIG. 1E is a model of the first 7 days of the dosing of FIG. 1D showing accumulation to steady state. FIG. 1F is a model of a 750 mg once daily dose of LYT-100 (total daily dose of 750 mg) and
its metabolites on day 7. FIG. 1G is a model of the first 7 days of the dosing of FIG. 1F showing accumulation to steady state.
FIG. 2 depicts representative micrographs of Sirius-red stained liver sections illustrating
that LYT-100 significantly reduced the area of fibrosis.
FIG. 3 illustrates the percent fibrosis area for LYT-100 versus vehicle and control.
FIG. 4A illustrates that LYT-100 does not induce survival of Primary Mouse Lung Fibroblasts
(PMFL); FIG 4B. and FIG. 4C illustrate LYT-100 reduced TGF-β-induced total collagen level in PMFL a 6 well and
96 well format, respectively; and FIG. 4D and FIG. 4E illustrate LYT-100 reduced TGF-β-induced soluble fibronectin levels and soluble collagen
levels.
FIG. 5A illustrates that LYT-100 does not affect survival of L929 cells. FIG. 5B, illustrates that LYT-100 inhibits TGF-induced collagen synthesis. FIG. 5C illustrates that LYT-100 significanly inhibits TGF-β-induced total collagen levels.
FIG. 5D is a graph illustrating that LYT-100 significantly inhibits TGF-β-induced soluble
collagen levels. FIG. 5E illustrates that LYT-100 signficantly reduced soluble fibronectin levels, in the
absence and presence of TGF-β-induction.
DETAILED DESCRIPTION OF THE INVENTION
1. General Description of Certain Aspects of the Invention
Deuterium-Enriched Pirfenidone
[0047] Pirfenidone (Deskar
®),
CAS# 53179-13-8, Pirespa, AMR-69, Pirfenidona, Pirfenidonum, Esbriet, Pirfenex, 5-methyl-1-phenyl-1
H-pyridin-2-one, 5-Methyl-1-phenyl-2-(1
H)-pyridone, 5-methyl-1-phenylpyridin-2(1
H)-one, is an orally administered antifibrotic agent. Pirfenidone is currently approved
in the United States and elsewhere for idiopathic pulmonary fibrosis (IPF).

[0048] The metabolism of pirfenidone is only partially understood. For example, without
wishing to be bound by theory, the methyl group is thought to be susceptible to oxidation,
which would lead to a corresponding hydroxymethyl metabolite, "M1." M1 is thought
to be further oxidized to a carboxylic acid metabolite, "M2" (
Wang et al., Biomedical Chromatography 2006, 20, 1375-1379). A third detected metabolite is believed to be a phase II product possibly originating
from M1 or M2. Pirfenidone has a very short half-life in humans.
Deuterium Kinetic Isotope Effect
[0049] In order to eliminate foreign substances from their circulation system, animal tissues
express various enzymes, such as the cytochrome P
450 enzymes or CYPs, esterases, proteases, reductases, dehydrogenases, and monoamine
oxidases, to react with and convert these foreign substances to more polar intermediates
or metabolites for renal excretion. Some of the most common metabolic reactions of
pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C-H) bond to
either a carbon-oxygen (C-O) or carbon-carbon (C-C) pi-bond. The resultant metabolites
may be stable or unstable under physiological conditions, and can have substantially
different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles
relative to the parent compounds. For most drugs, such oxidations are generally rapid
and ultimately require administration of multiple or high daily doses to maintain
therapeutically-effective levels of the drugs in patients.
[0050] The relationship between the activation energy and the rate of reaction may be quantified
by the Arrhenius equation, k=Ae
-Eact/RT, where E
act is the activation energy, T is temperature, R is the molar gas constant, k is the
rate constant for the reaction, and A (the frequency factor) is a constant specific
to each reaction that depends on the probability that the molecules will collide with
the correct orientation. The Arrhenius equation states that the fraction of molecules
that have enough energy to overcome an energy barrier, that is, those with energy
at least equal to the activation energy, depends exponentially on the ratio of the
activation energy to thermal energy (RT), the average amount of thermal energy that
molecules possess at a certain temperature.
[0051] The transition state in a reaction is a short lived state (on the order of 10
-14 sec) along the reaction pathway during which the original bonds have stretched to
their limit. By definition, the activation energy E
act for a reaction is the energy required to reach the transition state of that reaction.
Reactions that involve multiple steps will necessarily have a number of transition
states, and in these instances, the activation energy for the reaction is equal to
the energy difference between the reactants and the most unstable transition state.
Once the transition state is reached, the molecules can either revert, thus reforming
the original reactants, or the new bonds form giving rise to the products. This dichotomy
is possible because both pathways, forward and reverse, result in the release of energy.
A catalyst facilitates a reaction process by lowering the activation energy leading
to a transition state. Enzymes are examples of biological catalysts that reduce the
energy necessary to achieve a particular transition state.
[0052] A carbon-hydrogen bond is by nature a covalent chemical bond. Such a bond forms when
two atoms of similar electronegativity share some of their valence electrons, thereby
creating a force that holds the atoms together. This force or bond strength can be
quantified and is expressed in units of energy, and as such, covalent bonds between
various atoms can be classified according to how much energy must be applied to the
bond in order to break the bond or separate the two atoms.
[0053] The bond strength is directly proportional to the absolute value of the ground-state
vibrational energy of the bond. This vibrational energy, which is also known as the
zero-point vibrational energy, depends on the mass of the atoms that form the bond.
The absolute value of the zero-point vibrational energy increases as the mass of one
or both of the atoms making the bond increases. Since deuterium (D) is two-fold more
massive than hydrogen (H), it follows that a C-D bond is stronger than the corresponding
C-H bond. Compounds with C-D bonds are frequently indefinitely stable in H
2O, and have been widely used for isotopic studies. If a C-H bond is broken during
a rate-determining step in a chemical reaction (i.e. the step with the highest transition
state energy), then substituting a deuterium for that hydrogen will cause a decrease
in the reaction rate and the process will slow down. This phenomenon is known as the
Deuterium Kinetic Isotope Effect (DKIE) and can range from about 1 (no isotope effect)
to very large numbers, such as 50 or more, meaning that the reaction can be fifty,
or more, times slower when deuterium is substituted for hydrogen. High DKIE values
may be due in part to a phenomenon known as tunneling, which is a consequence of the
uncertainty principle. Tunneling is ascribed to the small size of a hydrogen atom,
and occurs because transition states involving a proton can sometimes form in the
absence of the required activation energy. A deuterium is larger and statistically
has a much lower probability of undergoing this phenomenon. Substitution of tritium
for hydrogen results in yet a stronger bond than deuterium and gives numerically larger
isotope effects.
[0054] Discovered in 1932 by Urey, deuterium (D) is a stable and non-radioactive isotope
of hydrogen. It was the first isotope to be separated from its element in pure form
and is twice as massive as hydrogen, and makes up about 0.02% of the total mass of
hydrogen (in this usage meaning all hydrogen isotopes) on earth. When two deuteriums
bond with one oxygen, deuterium oxide (D
2O or "heavy water") is formed.
Deuterated Pyridinone Derivatives
[0055] Pirfenidone is a substituted pyridinone-based fibrosis modulator and/or collagen
infiltration modulator. The carbon-hydrogen bonds of pirfenidone contain a naturally
occurring distribution of hydrogen isotopes, namely
1H or protium (about 99.9844%),
2H or deuterium (about 0.0156%), and
3H or tritium (in the range between about 0.5 and 67 tritium atoms per 10
18 protium atoms). Increased levels of deuterium incorporation may produce a detectable
Kinetic Isotope Effect (KIE) that could affect the pharmacokinetic, pharmacologic
and/or toxicologic profiles of such fibrosis modulators and/or collagen-infiltration
modulators in comparison with the compound having naturally occurring levels of deuterium.
[0056] Pirfenidone is likely metabolized in humans by oxidation of the methyl group. Other
sites on the molecule may also undergo transformations leading to metabolites with
as-yet-unknown pharmacology/toxicology. Limiting the production of these metabolites
has the potential to decrease the danger of the administration of such drugs and may
even allow increased dosage and concomitant increased efficacy. All of these transformations
can occur through polymorphically-expressed enzymes, thus exacerbating the interpatient
variability.
[0057] Various deuteration patterns can be used to a) reduce or eliminate unwanted metabolites,
b) increase the half-life of the parent drug, c) decrease the number of doses needed
to achieve a desired effect, d) decrease the amount of a dose needed to achieve a
desired effect, e) increase the formation of active metabolites, if any are formed,
and/or f) decrease the production of deleterious metabolites in specific tissues and/or
create a more effective drug and/or a safer drug for polypharmacy, whether the polypharmacy
be intentional or not. The deuteration approach has strong potential to slow the metabolism
via various oxidative and racemization mechanisms.
[0058] In one aspect, the present invention provides deuterium-enriched pirfenidone having
the structure shown in Formula
I:

or a pharmaceutically acceptable salt thereof, wherein:
[0059] R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 are selected from hydrogen and deuterium; and at least one of R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 is deuterium. In some embodiments, when R
7, R
8, R
9, R
10, and R
11 are deuterium, then at least one of R
1, R
2, R
3, R
4, R
5, and R
6 is deuterium.
[0060] In some embodiments, at least one of R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 independently has deuterium enrichment of no less than about 1%, no less than about
5%, no less than about 10%, no less than about 20%, no less than about 50%, no less
than about 70%, no less than about 80%, no less than about 90%, no less than about
95%, no less than about 96%, no less than about 97 %, no less than about 98%, no less
than about 99%, no less than about 99.1%, no less than about 99.2%, no less than about
99.3%, no less than about 99.4%, no less than about 99.5%, no less than about 99.6%,
no less than about 99.7%, no less than about 99.8%, or no less than about 99.9%. In
some embodiments, including any of the deuterium-enriched pirfenidone compounds described
below and elsewhere herein, at least one of R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 independently has deuterium enrichment of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %,
98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 100% or any
incremental numerical fraction within the stated deuterium enrichments.
[0061] In yet another embodiment, at least one of R
1, R
2, and R
3 is deuterium.
[0062] In yet another embodiment, at least two of R
1, R
2, and R
3 are deuterium.
[0063] In yet another embodiment, R
1, R
2, and R
3 are deuterium.
[0064] In yet another embodiment, R
4 is deuterium.
[0065] In yet another embodiment, at least one of R
5 and R
6 is deuterium.
[0066] In yet another embodiment, R
5 and R
6 are deuterium.
[0067] In yet another embodiment, R
5 and R
6 are deuterium; and at least one of R
1, R
2, R
3, R
4, R
7, R
8, R
9, R
10, and R
11 is deuterium.
[0068] In yet another embodiment, at least one of R
7, R
8, R
9, R
10, and R
11 is deuterium.
[0069] In yet another embodiment, R
7, R
8, R
9, R
10, and R
11 are deuterium.
[0070] In yet another embodiment, R
7, R
8, and R
9, are deuterium, and at least one of R
1, R
2, R
3, R
4, R
5, R
6, R
10, and R
11 is deuterium.
[0071] In yet another embodiment, at least one of R
1, R
2, and R
3 is deuterium; and R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 are hydrogen.
[0072] In yet another embodiment, at least two of R
1, R
2, and R
3 is deuterium; and R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 are hydrogen.
[0073] In yet another embodiment, R
1, R
2, and R
3 are deuterium; and R
4, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 are hydrogen.
[0074] In yet another embodiment, R
4 is deuterium; and R
1, R
2, R
3, R
5, R
6, R
7, R
8, R
9, R
10, and R
11 are hydrogen.
[0075] In yet another embodiment, at least one of R
5 and R
6 is deuterium; and R
1, R
2, R
3, R
4, R
7, R
8, R
9, R
10, and R
11 are hydrogen.
[0076] In yet another embodiment, R
5 and R
6 are deuterium; and R
1, R
2, R
3, R
4, R
7, R
8, R
9, R
10, and R
11 are hydrogen.
[0077] In yet another embodiment, at least one of R
1, R
2, R
3, R
4, R
5, and R
6 is deuterium; and R
7, R
8, R
9, R
10, and R
11 are hydrogen.
[0078] In yet another embodiment, R
1, R
2, R
3, R
4, R
5, and R
6 are deuterium; and R
7, R
8, R
9, R
10, and R
11 are hydrogen.
[0079] In yet another embodiment, at least one of R
7, R
8, R
9, R
10, and R
11 is deuterium; and R
1, R
2, R
3, R
4, R
5, and R
6 are hydrogen.
[0080] In yet another embodiment, R
7, R
8, R
9, R
10, and R
11 are deuterium; and at least one of R
1, R
2, R
3, R
4, R
5, and R
6 is deuterium.
[0081] In other embodiments, R
1 is hydrogen. In yet other embodiments, R
2 is hydrogen. In still other embodiments, R
3 is hydrogen. In yet other embodiments, R
4 is hydrogen. In some embodiments, R
5 is hydrogen. In yet other embodiments, R
6 is hydrogen. In still other embodiments, R
7 is hydrogen. In still other embodiments, R
8 is hydrogen. In some embodiments, R
9 is hydrogen. In other embodiments, R
10 is hydrogen. In yet other embodiments, R
11 is hydrogen.
[0082] In other embodiments, R
1 is deuterium. In yet other embodiments, R
2 is deuterium. In still other embodiments, R
3 is deuterium. In yet other embodiments, R
4 is deuterium. In some embodiments, R
5 is deuterium. In yet other embodiments, R
6 is deuterium. In still other embodiments, R
7 is deuterium. In still other embodiments, R
8 is deuterium. In some embodiments, R
9 is deuterium. In other embodiments, R
10 is deuterium. In yet other embodiments, R
11 is deuterium.
[0083] In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically
acceptable salt thereof. LYT-100 has the following structure:

[0084] In some embodiments, the deuterium-enriched pirfenidone is a compound or pharmaceutically
acceptable salt thereof, or a metabolite thereof, described in
WO 2008/157786,
WO 2009/035598,
WO 2012/122165, or
WO 2015/112701, the entireties of which are hereby incorporated by reference.
[0085] In one aspect, the present invention provides a deuterium-enriched compound shown
in
Table 1, or a pharmaceutically acceptable salt thereof:

[0086] In some embodiments, the present invention provides a compound as depicted in
Table 1, above, or a pharmaceutically acceptable salt thereof.
[0087] In some embodiments, the present invention provides a compound as depicted in
Table 1, above, or a pharmaceutically acceptable salt thereof, wherein at least one of the
positions represented as D independently has deuterium enrichment of no less than
about 1%, no less than about 5%, no less than about 10%, no less than about 20%, no
less than about 50%, no less than about 70%, no less than about 80%, no less than
about 90%, no less than about 95%, no less than about 96%, no less than about 97 %,
no less than about 98%, no less than about 99%, no less than about 99.1%, no less
than about 99.2%, no less than about 99.3%, no less than about 99.4%, no less than
about 99.5%, no less than about 99.6%, no less than about 99.7%, no less than about
99.8%, or no less than about 99.9%. In other embodiments, at least one of the positions
represented as D independently has deuterium enrichment of 90%, 91%, 92%, 93%, 94%,
95%, 96%, 97 %, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%,
99.9%, 100% or any incremental numerical fraction within the stated deuterium enrichments.
[0088] In a further embodiment, said compound is substantially a single enantiomer, a mixture
of about 90% or more by weight of the (-)-enantiomer and about 10% or less by weight
of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer
and about 10% or less by weight of the (-)-enantiomer, substantially an individual
diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer
and about 10% or less by weight of any other diastereomer.
[0089] In certain embodiments, the compound as disclosed herein contains about 60% or more
by weight of the (-)-enantiomer of the compound and about 40% or less by weight of
(+)-enantiomer of the compound. In certain embodiments, the compound as disclosed
herein contains about 70% or more by weight of the (-)-enantiomer of the compound
and about 30% or less by weight of (+)-enantiomer of the compound. In certain embodiments,
the compound as disclosed herein contains about 80% or more by weight of the (-)-enantiomer
of the compound and about 20% or less by weight of (+)-enantiomer of the compound.
In certain embodiments, the compound as disclosed herein contains about 90% or more
by weight of the (-)-enantiomer of the compound and about 10% or less by weight of
the (+)-enantiomer of the compound. In certain embodiments, the compound as disclosed
herein contains about 95% or more by weight of the (-)-enantiomer of the compound
and about 5% or less by weight of (+)-enantiomer of the compound. In certain embodiments,
the compound as disclosed herein contains about 99% or more by weight of the (-)-enantiomer
of the compound and about 1% or less by weight of (+)-enantiomer of the compound.
[0090] In certain embodiments, the compound as disclosed herein contains about 60% or more
by weight of the (+)-enantiomer of the compound and about 40% or less by weight of
(-)-enantiomer of the compound. In certain embodiments, the compound as disclosed
herein contains about 70% or more by weight of the (+)-enantiomer of the compound
and about 30% or less by weight of (-)-enantiomer of the compound. In certain embodiments,
the compound as disclosed herein contains about 80% or more by weight of the (+)-enantiomer
of the compound and about 20% or less by weight of (-)-enantiomer of the compound.
In certain embodiments, the compound as disclosed herein contains about 90% or more
by weight of the (+)-enantiomer of the compound and about 10% or less by weight of
the (-)-enantiomer of the compound. In certain embodiments, the compound as disclosed
herein contains about 95% or more by weight of the (+)-enantiomer of the compound
and about 5% or less by weight of (-)-enantiomer of the compound. In certain embodiments,
the compound as disclosed herein contains about 99% or more by weight of the (+)-enantiomer
of the compound and about 1% or less by weight of (-)-enantiomer of the compound.
[0091] The deuterated compound as disclosed herein may also contain less prevalent isotopes
for other elements, including, but not limited to,
13C or
14C for carbon,
15N for nitrogen, and
17O or
18O for oxygen.
[0092] Isotopic hydrogen can be introduced into a compound of a compound disclosed herein
as disclosed herein by synthetic techniques that employ deuterated reagents, whereby
incorporation rates are pre-determined; and/or by exchange techniques, wherein incorporation
rates are determined by equilibrium conditions, and may be highly variable depending
on the reaction conditions. Synthetic techniques, where tritium or deuterium is directly
and specifically inserted by tritiated or deuterated reagents of known isotopic content,
may yield high tritium or deuterium abundance, but can be limited by the chemistry
required. In addition, the molecule being labeled may be changed, depending upon the
severity of the synthetic reaction employed. Exchange techniques, on the other hand,
may yield lower tritium or deuterium incorporation, often with the isotope being distributed
over many sites on the molecule, but offer the advantage that they do not require
separate synthetic steps and are less likely to disrupt the structure of the molecule
being labeled.
[0093] The compounds as disclosed herein can be prepared by methods known to one of skill
in the art and routine modifications thereof, and/or procedures found in
Esaki et al., Tetrahedron 2006, 62, 10954-10961,
Smith et al., Organic Syntheses 2002, 78, 51-56,
U.S. Pat. No. 3,974,281,
U.S. Pat. No. 8,680,123,
WO2003/014087,
WO 2008/157786,
WO 2009/035598,
WO 2012/122165, or
WO 2015/112701; the entirety of each of which is hereby incorporated by reference; and references
cited therein and routine modifications thereof.
Methods, Compositions and Dosing for Treating Fibrotic-mediated Disorders and/or a Collagen-mediated Disorders
[0094] Disclosed herein are methods for the treatment, prevention, and/or amelioration of
a fibrotic-mediated disorder and/or a collagen-mediated disorder and/or inflammatory
disorder comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound disclosed herein, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100. Disclosed herein are methods
for the treatment, prevention, and/or amelioration of one or more symptoms of a fibrotic-mediated
disorder and/or a collagen-mediated disorder and/or inflammatory disorder comprising
administering to a subject in need thereof a deuterium-enriched pirfenidone compound
disclosed herein, for example, a compound of Formula I, e.g., a compound listed in
Table 1, including e.g., LYT-100. Disclosed herein are methods for the treatment,
prevention, and/or amelioration of a fibrotic-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100. Disclosed herein are methods for the treatment, prevention, and/or
amelioration of one or more symptoms of a fibrotic-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100. Disclosed herein are methods for the treatment, prevention, and/or
amelioration of a collagen-mediated disorder comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100.
Disclosed herein are methods for the treatment, prevention, and/or amelioration of
one or more symptoms of a collagen-mediated disorder comprising administering to a
subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100. Disclosed herein are methods for the treatment, prevention, and/or
amelioration of an inflammatory disorder comprising administering to a subject in
need thereof a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100.
Disclosed herein are methods for the treatment, prevention, and/or amelioration of
one or more symptoms of an inflammatory disorder comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100.
[0095] A fibrotic-mediated disorder and/or a collagen-mediated disorder include, but are
not limited to, idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis,
renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial
hepatectomy or hepatic ischemia, allograft injury after organ transplantation, cystic
fibrosis, atrial fibrilation, neutropenia, scleroderma, dermatomyositis, cirrhosis,
diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, spleen fibrosis
caused by sickle-cell anemia, rheumatoid arthritis, edema, lymphedema, and/or any
disorder ameliorated by modulating fibrosis and/or collagen infiltration into tissues.
[0096] In some embodiments, the deuterium-enriched pirfenidone compound used in the disclosed
methods has at least one of the following properties: a) decreased inter-individual
variation in plasma levels of the compound or a metabolite thereof as compared to
the non-isotopically enriched compound; b) increased average plasma levels of the
compound per dosage unit thereof as compared to the non-isotopically enriched compound;
c) decreased average plasma levels of at least one metabolite of the compound per
dosage unit thereof as compared to the non-isotopically enriched compound; d) increased
average plasma levels of at least one metabolite of the compound per dosage unit thereof
as compared to the non-isotopically enriched compound; and e) an improved clinical
effect during the treatment in the subject per dosage unit thereof as compared to
the non-isotopically enriched compound. Thus, disclosed herein are methods for treating
a subject, including a human, having or suspected of having a fibrotic-mediated disorder
and/or a collagen-mediated disorder (e.g., any of the disorders disclosed herein)
or for preventing such disorder in a subject prone to the disorder; comprising administering
to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone
compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug
thereof; so as to effect one or more of a) - e) above during the treatment of the
disorder as compared to the corresponding non-isotopically enriched compound. In some
embodiments, the deuterium-enriched pirfenidone compound has at least two of the properties
a) through e) above. In some embodiments, the deuterium-enriched pirfenidone compound
has three or more of the properties a) through e) above.
[0097] In one embodiment is a method for the treatment, prevention, or amelioration of one
or more symptoms of a fibrotic-mediated disorder and/or a collagen-mediated disorder.
A fibrotic-mediated disorder and/or a collagen-mediated disorder include, but are
not limited to, idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis,
renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial
hepatectomy or hepatic ischemia, allograft injury after organ transplantation, cystic
fibrosis, atrial fibrilation, neutropenia, scleroderma, dermatomyositis, cirrhosis,
diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, spleen fibrosis
caused by sickle-cell anemia, rheumatoid arthritis, and/or any disorder ameliorated
by modulating fibrosis and/or collagen infiltration into tissues.
[0098] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder
(e.g., any of the disorders disclosed herein) or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to effect
decreased inter-individual variation in plasma levels of the compound or a metabolite
thereof, during the treatment of the disorder as compared to the corresponding non-isotopically
enriched compound. In certain embodiments, the inter-individual variation in plasma
levels of the compounds as disclosed herein, or metabolites thereof, is decreased
by greater than about 2%, greater than about 5%, greater than about 10%, greater than
about 15%, greater than about 20%, greater than about 25%, greater than about 30%,
greater than about 40%, or by greater than about 50% (including any numerical increment
between the listed percentages) as compared to the corresponding non-isotopically
enriched compound.
[0099] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder
(e.g., any of the disorders disclosed herein) or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to affect
increased average plasma levels of the compound or decreased average plasma levels
of at least one metabolite of the compound per dosage unit as compared to the corresponding
non-isotopically enriched compound. In certain embodiments, the average plasma levels
of the compound as disclosed herein are increased by greater than about 2%, greater
than about 5%, greater than about 10%, greater than about 15%, greater than about
20%, greater than about 25%, greater than about 30%, greater than about 40%, or by
greater than about 50% (including any numerical increment between the listed percentages)
as compared to the corresponding non-isotopically enriched compounds. In certain embodiments,
the average plasma levels of a metabolite of the compound as disclosed herein are
decreased by greater than about 2%, greater than about 5%, greater than about 10%,
greater than about 15%, greater than about 20%, greater than about 25%, greater than
about 30%, greater than about 40%, or by greater than about 50% (including any numerical
increment between the listed percentages) as compared to the corresponding non-isotopically
enriched compounds.
[0101] In some embodiments, the compound has a decreased metabolism by at least one polymorphically-expressed
cytochrome P
450 isoform in the subject per dosage unit thereof as compared to the non-isotopically
enriched compound.
[0102] In some embodiments, the cytochrome P
450 isoform is selected from CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
[0103] In some embodiments, the compound is characterized by decreased inhibition of at
least one cytochrome P
450 or monoamine oxidase isoform in the subject per dosage unit thereof as compared to
the non-isotopically enriched compound.
[0104] In certain embodiments, the cytochrome P
450 or monoamine oxidase isoform is selected from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13,
CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1,
CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3,
CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1,
CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1,
CYP27B1, CYP39, CYP46, CYP51, MAO
A, and MAO
B.
[0105] In some embodiments, the deuterium-enriched pirfenidone compound has at least one
of the following properties: a) a half-life greater than 2.5 hours; b) a decreased
pill burden; c) increased patient tolerability; d) a lower efficacious dose; e) increased
bioavailability; f) increased Cmax; and g) increase in systemic exposure during the
treatment in the subject per dosage unit thereof as compared to the non-isotopically
enriched compound. Disclosed herein are methods for treating a subject, including
a human, having or suspected of having a fibrotic-mediated disorder and/or a collagen-mediated
disorder (e.g., any of the disorders disclosed herein) or for preventing such disorder
in a subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to effect
one or more of a) - g) above during the treatment of the disorder as compared to the
corresponding non-isotopically enriched compound.
[0106] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder
(e.g., any of the disorders disclosed herein) or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to effect
a longer half-life. In some embodiments, the half-life of the deuterium-enriched pirfenidone
compounds as disclosed herein, or metabolites thereof, is increased by greater than
about 2%, greater than about 5%, greater than about 10%, greater than about 15%, greater
than about 20%, greater than about 25%, greater than about 30%, greater than about
40%, by greater than about 50%, by greater than about 60%, by greater than about 70%,
by greater than about 80%, by greater than about 90%, or by greater than about 100%
(including any numerical increment between the listed percentages) as compared to
the corresponding non-isotopically enriched compound. In some embodiments, the half-life
of the deuterium-enriched pirfenidone compounds as disclosed herein, or metabolites
thereof, is increased by about 1.5-fold, increased by about 2-fold, greater than about
2-fold, greater than about 3-fold, greater than about 4-fold, greater than about greater
than about 5-fold, greater than about 10-fold or more (including any numerical increment
between the listed percentages) as compared to the corresponding non-isotopically
enriched compound.
[0107] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder
(e.g., any of the disorders disclosed herein) or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to reduce
the pill burden, e.g., effect a pill burden of less than nine (9) capsules per day
(TID dosing) of the compound or a metabolite thereof, during the treatment of the
disorder as compared to the corresponding non-isotopically enriched compound.
[0108] In certain embodiments, the pill burden of the compounds as disclosed herein, is
decreased by greater than about 2%, greater than about 5%, greater than about 10%,
greater than about 15%, greater than about 20%, greater than about 25%, greater than
about 30%, greater than about 40%, or by greater than about 50% (including any numerical
increment between the listed percentages) as compared to the corresponding non-isotopically
enriched compound.
[0109] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder
(e.g., any of the disorders disclosed herein) or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to effect
an increased patient tolerability of the compound or a metabolite thereof, during
the treatment of the disorder as compared to the corresponding non-isotopically enriched
compound. In some embodiments, the patient tolerability is increased by altering the
pharmacokinetics, e.g., by increasing the bioavailability (so as to use a lower dose)
and/or by extending the half-life of the compound and/or by other means to reduce
the side effects of pirfenidone.
[0110] In certain embodiments, the patient tolerability of the compounds as disclosed herein,
or metabolites thereof, is increased by greater than about 2%, greater than about
5%, greater than about 10%, greater than about 15%, greater than about 20%, greater
than about 25%, greater than about 30%, greater than about 40%, by greater than about
50%, by greater than about 60%, by greater than about 70%, by greater than about 80%,
by greater than about 90%, or by greater than about 100% (including any numerical
increment between the listed percentages) as compared to the corresponding non-isotopically
enriched compound. In certain embodiments, the patient tolerability of the compounds
as disclosed herein, or metabolites thereof, is increased by about 1.5-fold, increased
by about 2-fold, greater than about 2-fold, greater than about 3-fold, greater than
about 4-fold, greater than about greater than about 5-fold, greater than about 10-fold
or more (including any numerical increment between the listed percentages) as compared
to the corresponding non-isotopically enriched compound.
[0111] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder
(e.g., any of the disorders disclosed herein) or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to effect
a lower efficacious dose per dosage of the compound or a metabolite thereof, during
the treatment of the disorder as compared to the corresponding non-isotopically enriched
compound.
[0112] In certain embodiments, the efficacious dose per dosage of the compounds as disclosed
herein, or metabolites thereof, is decreased by greater than about 2%, greater than
about 5%, greater than about 10%, greater than about 15%, greater than about 20%,
greater than about 25%, greater than about 30%, greater than about 40%, by greater
than about 50%, by greater than about 60%, by greater than about 70%, by greater than
about 80%, by greater than about 90%, or by greater than about 100% (including any
numerical increment between the listed percentages) as compared to the corresponding
non-isotopically enriched compound. In certain embodiments, the efficacious dose per
dosage of the compounds as disclosed herein, or metabolites thereof, is decreased
by about 1.5-fold, decreased by about 2-fold, greater than about 2-fold, greater than
about 3-fold, greater than about 4-fold, greater than about greater than about 5-fold,
greater than about 10-fold or more (including any numerical increment between the
listed percentages) as compared to the corresponding non-isotopically enriched compound.
[0113] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder
(e.g., any of the disorders disclosed herein) or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to increase
the bioavailability per dosage of the compound or a metabolite thereof, during the
treatment of the disorder as compared to the corresponding non-isotopically enriched
compound.
[0114] In certain embodiments, the bioavailability per dosage of the compounds as disclosed
herein, or metabolites thereof, is increased by greater than about 2%, greater than
about 5%, greater than about 10%, greater than about 15%, greater than about 20%,
greater than about 25%, greater than about 30%, greater than about 40%, by greater
than about 50%, by greater than about 60%, by greater than about 70%, by greater than
about 80%, by greater than about 90%, or by greater than about 100% (including any
numerical increment between the listed percentages) as compared to the corresponding
non-isotopically enriched compound. In certain embodiments, the bioavailability per
dosage of the compounds as disclosed herein, or metabolites thereof, is increased
by about 1.5-fold, decreased by about 2-fold, greater than about 2-fold, greater than
about 3-fold, greater than about 4-fold, greater than about greater than about 5-fold,
greater than about 10-fold or more (including any numerical increment between the
listed percentages) as compared to the corresponding non-isotopically enriched compound.
[0115] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having or suspected of having a fibrotic-mediated disorder and/or a collagen-mediated
disorder (e.g., any of the disorders disclosed herein) or for preventing such disorder
in a subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to affect
an increase in systemic exposure of the compound per dosage unit as compared to the
corresponding non-isotopically enriched compound.
[0116] In certain embodiments, the systemic exposure per dosage of the compounds as disclosed
herein, or metabolites thereof, is increased by greater than about 10%, greater than
about 15%, greater than about 20%, greater than about 25%, greater than about 30%,
greater than about 35%, greater than about 40%, greater than about 45%, or by greater
than about 50% (including any numerical increment between the listed percentages)
as compared to the corresponding non-isotopically enriched compound. In one embodiment,
the systemic exposure per dosage of the compounds as disclosed herein is increased
by greater than about 35% as compared to the corresponding non-isotopically enriched
compound. In one embodiment, the systemic exposure per dosage of the compounds as
disclosed herein is increased by about 35% as compared to the corresponding non-isotopically
enriched compound.
[0117] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having or suspected of having a fibrotic-mediated disorder and/or a collagen-mediated
disorder (e.g., any of the disorders disclosed herein) or for preventing such disorder
in a subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to affect
an increase in Cmax of the compound per dosage unit as compared to the corresponding
non-isotopically enriched compound.
[0118] In certain embodiments, the Cmax per dosage of the compounds as disclosed herein,
or metabolites thereof, is increased by greater than about 10%, greater than about
15%, greater than about 20%, greater than about 25%, greater than about 30%, greater
than about 35%, greater than about 40%, greater than about 45%, or by greater than
about 50% (including any numerical increment between the listed percentages) as compared
to the corresponding non-isotopically enriched compound. In one embodiment, the Cmax
per dosage of the compounds as disclosed herein is increased by greater than about
25% as compared to the corresponding non-isotopically enriched compound. In one embodiment,
the Cmax per dosage of the compounds as disclosed herein is increased by about 25%
as compared to the corresponding non-isotopically enriched compound.
[0119] In some embodiments, the method treats the disorder while reducing or eliminating
a deleterious change in a diagnostic hepatobiliary function endpoint, as compared
to the corresponding non-isotopically enriched compound, e.g., pirfenidone. Disclosed
herein are methods for treating a subject, including a human, having or suspected
of having a fibrotic-mediated disorder and/or a collagen-mediated disorder (e.g.,
any of the disorders disclosed herein) or for preventing such disorder in a subject
prone to the disorder; comprising administering to the subject a therapeutically effective
amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate,
or prodrug thereof; so as to reduce or eliminate a deleterious change in a diagnostic
hepatobiliary function endpoint, as compared to the corresponding non-isotopically
enriched compound. In some embodiments, the diagnostic hepatobiliary function endpoint
is selected from alanine aminotransferase ("ALT"), serum glutamic-pyruvic transaminase
("SGPT"), aspartate aminotransferase ("AST," "SCOT"), ALT/AST ratios, serum aldolase,
alkaline phosphatase ("ALP"), ammonia levels, bilirubin, gamma-glutamyl transpeptidase
("GGTP," "gamma-GTP," "GGT"), leucine aminopeptidase ("LAP"), liver biopsy, liver
ultrasonography, liver nuclear scan, 5'-nucleotidase, and blood protein.
[0120] Disclosed herein are methods for the treatment, prevention, and/or amelioration of
a fibrotic-mediated disorder and/or a collagen-mediated disorder and methods for the
treatment, prevention, and/or amelioration of one or more symptoms of a fibrotic-mediated
disorder and/or a collagen-mediated disorder comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
and further comprising administering one or more additional therapeutic agent(s) selected
from an anti-T cell agent, an anti-inflammatory agent, an anti-TGF-βI agent, and an
anti-angiotensin agent. In some embodiments, the additional therapeutic agent is an
anti-inflammatory agent. In some embodiments, the additional therapeutic agent is
an anti-T-cell agent. In some embodiments, the additional therapeutic agent is an
anti-TGF-βI agent. In some embodiments, the additional therapeutic agent is an anti-angiotensin
agent.
[0121] In some embodiments, the therapeutic agent is deuterium-enriched pirfenidone, or
a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent
is LYT-100, or a pharmaceutically acceptable salt thereof. In some embodiments, the
therapeutic agent is deuterium-enriched pirfenidone, or a pharmaceutically acceptable
salt thereof, in combination with one or more additional therapeutic agents, such
as any of the additional therapeutic agents disclosed herein.
[0122] In any of the above-described embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is administered orally twice a day, for a total daily dose of 100-1500
mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700,
750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In
some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is
750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily
dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is administered
orally 750 mg twice daily. In some embodiments, the deuterium-enriched pirfenidone
is administered orally 500 mg twice daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 250 mg twice daily.
[0123] In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100,
is administered orally once a day, for a total daily dose of 100-1500 mg. In some
embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900,
1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments,
the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some
embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250
mg. In some embodiments, the deuterium-enriched pirfenidone is administered orally
1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone is administered
orally 1000 mg once daily. In some embodiments, the deuterium-enriched pirfenidone
is administered orally 750 mg once daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 500 mg once daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 250 mg once daily.
[0124] In any of the above-described embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100 is administered orally three times a day, for a total daily dose of
100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500,
600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is
1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the
daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments,
the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone
is administered orally 500 mg three times daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 333 mg three times daily. In some embodiments,
the deuterium-enriched pirfenidone is administered orally 166 mg three times daily.
[0125] In some embodiments, the deuterium-enriched pirfenidone is in tablet form. In some
embodiments, the deuterium-enriched pirfenidone is taken orally with food.
[0126] Thus, provided herein are methods for the treatment, prevention, and/or amelioration
of a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
wherein the deuterium-enriched pirfenidone compound is administered orally twice a
day, for a total daily dose of 100-1500 mg. In some embodiments, provided herein are
methods for the treatment, prevention, and/or amelioration of a fibrotic-mediated
disorder and/or a collagen-mediated disorder comprising administering to a subj ect
in need thereof LYT-100, wherein LYT-100 is administered orally twice a day, for a
total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1000 mg. In some
embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100 is 500 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100 is 250 mg. In some embodiments,
the deuterium-enriched pirfenidone compound, e.g., LYT-100 is administered orally
750 mg twice daily. In some embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is administered orally 500 mg twice daily. In some embodiments, the
deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally 250
mg twice daily.
[0127] In some embodiments, provided herein are methods for the treatment, prevention, and/or
amelioration of a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising
administering to a subject in need thereof a deuterirum-enriched pirfenidone compound,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, wherein the deuterirum-enriched pirfenidone compound is administered
orally once a day, for a total daily dose of 100-1500 mg. In some embodiments, provided
herein are methods for the treatment, prevention, and/or amelioration of a fibrotic-mediated
disorder and/or a collagen-mediated disorder comprising administering to a subject
in need thereof LYT-100, wherein LYT-100, is administered orally once a day, for a
total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100 is 1500 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1000 mg. In some
embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100 is 500 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 250 mg. In some
embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered
orally 1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone
compound, e.g., LYT-100, is administered orally 1000 mg once daily. In some embodiments,
the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally
750 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is administered orally 500 mg once daily. In some embodiments, the
deuterium-enriched pirfenidone compound, e.g., LYT-100 is administered orally 250
mg once daily.
[0128] Thus, provided herein are methods for the treatment, prevention, and/or amelioration
of a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
wherein the deuterium-enriched pirfenidone compound is administered orally three times
daily, for a total daily dose of 100-1500 mg. In some embodiments, provided herein
are methods for the treatment, prevention, and/or amelioration of a fibrotic-mediated
disorder and/or a collagen-mediated disorder comprising administering to a subject
in need thereof LYT-100, wherein LYT-100 is administered orally three times a day,
for a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the
deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments,
the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1000
mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100 is 500 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100 is 250 mg. In some embodiments,
the deuterium-enriched pirfenidone compound, e.g., LYT-100 is administered orally
500 mg three times daily. In some embodiments, the deuterium-enriched pirfenidone
compound, e.g., LYT-100, is administered orally 333 mg three timese daily. In some
embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered
orally 166 mg twice daily.
[0129] In other embodiments, the deuterium-enriched pirfenidone compound is administered
orally at a total daily dose of 100-2500 mg. In some embodiments, the deuterium-enriched
pirfenidone compound is administered orally at a total daily dose of 100-2000 mg.
In some embodiments, the deuterium-enriched pirfenidone compound is administered orally
at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-enriched
pirfenidone compound is administered orally at a total daily dose of 100-1000 mg.
In some embodiments, the deuterium-enriched pirfenidone compound is administered orally
at a total daily dose of 100-500 mg. In some embodiments, the daily dose is selected
from 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300,
1400, 1500, 1600, 1700,1800, 1900, 2000, 2100, 2200, 2300, 2400, and 2500 mg/day.
In some embodiments, the deuterium-enriched pirfenidone compound is administered orally
three times/day (TID). In some embodiments, the deuterium-enriched pirfenidone compound
is administered orally two times/day (BID). In some embodiments, the deuterium-enriched
pirfenidone compound is administered orally once daily (QD). In any of these embodiments,
the deuterium-enriched pirfenidone compound has the structire of Formula I, e.g.,
a compound listed in
Table 1, including e.g., LYT-100.
Methods, Compositions and Dosing for Treating Edema
[0130] The term "edema" or "oedema," as used herein, is an abnormal accumulation of fluid
beneath the skin and in body cavities including, but not limited to, limbs, hands/feet,
upper body (breast/chest wall, shoulder, back), lower body (buttocks, abdomen), genital
(scrotum, penis, vulva), head, neck, or face. The abnormal accumulation of fluid can
occur when capillary filtration exceeds lymphatic drainage. In this way, all edema
has a lymphatic component. Edema includes lymphedema, lymphatic dysfunction, lymphatic
tissue fibrosis, idiopathic edema, peripheral edema, and eye edema. Edema includes
acute edema, chronic edema, post-operative edema, gradual-onset edema, primary edema
and secondary edema. Chronic edema is edema that has been present for more than three
months and can include lymphedema (primary-failure of the lymphatic development and
secondary-following damage to the lymphatics), venous edema, chronic swelling due
to immobility, edema related to advanced cancer, chronic swelling associated with
lymphedema, chronic swelling related to obesity, and chronic swelling associated with
rare vascular malformations such as Klippel-Trenaunay syndrome. Symptoms of edema
can include accumulation of fluid beneath the skin and in body cavities, swelling,
fullness, or puffiness of tissues, inflammation, fibrosis, heaviness, pain, decreased
range of motion, aching, recurring infections, skin thickening, or discomfort. In
some embodiments, "edema" does not include pulmonary edema or cerebral edema. In some
embodiments, the edema is lymphedema. In some embodiments, the lymphedema is primary
lymphedema. In some embodiments, the lymphedema is secondary lymphedema.
[0131] Lymphedema is a chronic condition that afflicts millions of people and is characterized
by severe swelling in parts of the body, typically the arms or legs, due to the build-up
of lymph fluid and inflammation, fibrosis and adipose deposition. Lymph is a clear
fluid collected from body tissues that transports fats and proteins from the small
intestine, removes bacteria, viruses, toxins, and certain proteins from tissues and
supplies white blood cells, specifically lymphocytes, to the bloodstream to help fight
infections and other diseases. Lymphedema is a chronic debilitating disease of fibrotic
and inflammatory origin, that in developed countries, such as the United States, occurs
most often as a complication of cancer treatment. Thus, secondary lymphedema is the
most prevalent form of lymphedema, and can develop after surgery, infection or trauma,
and is frequently caused by cancer, cancer treatments such as radiation and chemotherapy,
trauma or infections resulting in damage to or the removal of lymph nodes. As a complication
of cancer treatment, lymphedema occurs as a result of iatrogenic injury to the lymphatic
system, usually as a result of lymph node dissection. According to estimates, as many
as 1 in 3 patients who undergo lymph node dissection later develop lymphedema. Large
skin excisions and adjuvant therapy with radiation may also cause lymphedema. In addition,
obesity and radiation are known risk factors for the development of lymphedema.
[0132] Lymphedema of the leg and its advanced form, known as elephantiasis, are significant
causes of disability and morbidity in areas endemic for lymphatic filariasis, with
an estimated 14 million persons affected worldwide (
Stocks et al., PLoS Negl Trop Dis. 2015 Oct 23;9(10):e0004171). Over 1.1 billion people worldwide are at risk for lymphatic filariasis (
Walsh et al, PLoS Negl Trop Dis. 2016 Aug 22;10(8):e0004917). Lymphatic filariasis is distributed from Latin America, across central Africa,
southern Asia and into the Pacific Islands. Filarial infection is mosquito-transmitted,
but efforts to control transmission that are based exclusively on mosquito control
have had limited success (
Lammie et al., Ann N Y Acad Sci. 2002 Dec;979:131-42; discussion 188-96). Wuchereria bancrofti (Wb) is the most widely distributed of
the three nematodes known to cause lymphatic filariasis (LF), the other two being
Brugia malayi and Brugia timori. Wuchereria bancrofti is the species responsible for
90% of lymphatic filariasis in humans. Filarial infection can cause a variety of clinical
manifestations, including lymphoedema of the limbs, genital disease (hydrocele, chylocele,
and swelling of the scrotum and penis) and recurrent acute attacks. These acute attacks
are caused by secondary infections, to which the lower limbs with lymphatic damage
are predisposed, and which are extremely painful and are accompanied by fever. Most
infected people do not have symptoms, but virtually all of them have subclinical lymphatic
damage and as many as 40% have kidney damage, with proteinuria and hematuria.
[0133] Lymphedema is a serious disease with significant health consequences, including disfigurement
and debilitation. Patients have chronic swelling of the affected extremity, a sense
of heaviness, pain, discomfort, skin damage, fibrosis, recurrent infections, limited
mobility, and decreased quality of life.
[0134] Dysfunctions of the lymphatic system have remained largely untreated or poorly addressed
by current therapeutics. There are currently no approved drug therapies for the treatment
of lymphedema. Furthermore, at present, there is no known pharmacologic therapy that
can halt progression or promote resolution of lymphedema. The current standard of
care for lymphedema is management, primarily with compression and physical therapy
to control swelling. These approaches are cumbersome, uncomfortable and non-curative,
and they do not address the underlying disease, especially in patients with more severe
lymphedema. Even with management, some patients will progress from mild-to-moderate
lymphedema to more severe forms. In later stages, patients may also seek ablative
surgeries, including liposuction or debulking. These surgeries reduce volume but do
not restore lymphatic flow, leading to a dependence on compression. Given that there
are currently no drug therapies that treat the underlying causes of lymphedema, the
development of targeted treatments for lymphedema is an unmet biomedical need.
[0135] There has been little progress toward the development of meaningful treatments for
lymphatic diseases. Previous experimental treatments for lymphedema have focused on
delivery of lymphangiogenic cytokines.
Skobe et al., Nat. Med. 7: 192-198 (2001). For example, some previous studies have focused on repairing damaged lymphatics
using lymphangiogenic cytokines such as vascular endothelial growth factor-c (VEGF-C).
Tammela et al., Nat. Med. 13: 1458-1466
[0136] (2007);
Baker et al., Breast Cancer Res. 12:R70 (2010). However, application of this approach, particularly to cancer patients, may be
untenable as these same mechanisms regulate tumor growth and metastasis, raising the
risk of cancer metastases or recurrence.
[0137] In some embodiments, the disclosure provides methods for treating edema comprising
administering to a subject in need thereof a deuterium-enriched pirfenidone compound
disclosed herein, for example, a compound of Formula I, e.g., a compound listed in
Table 1, including e.g., LYT-100. In some embodiments, the disclosure provides methods
for treating lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound disclosed herein, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100. In some embodiments, the disclosure
provides methods for treating secondary lymphedema comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100.
In some embodiments, the disclosure provides methods for treating primary lymphedema
comprising administering to a subject in need thereof a deuterium-enriched pirfenidone
compound disclosed herein, for example, a compound of Formula I, e.g., a compound
listed in Table 1, including e.g., LYT-100.
[0138] In some embodiments, the lymphedema occurs in one or both arms, such as in the hand,
wrist, forearm, elbow, upper arm, shoulder, armit, or combination of arm areas or
the entire arm. In some embodiments, the lymphedema occurs in one or both legs, such
as in the foot, ankle, leg, knee, upper leg or thigh, groin, hip, or combination of
leg areas or the entire leg. In some embodiments, the lymphedema occurs in the head,
neck, jaw, chest, breast, thorax, abdomen, pelvis, genitals, or other areas of the
body cavity. In some embodiments, the lymphedema occurs in one or more limbs, or in
one or more limbs and another area of the body.
[0139] In some embodiments the lymphedema results from a vascular defect, including venous
insufficiency, venous malformation, arterial malformation, capillary malformation,
lymphovascular malformation, or cardiovascular disease.
[0140] In some embodiments, the subject has or has had cancer, for example, a cancer comprising
a solid tumor. In some embodiments, the subject has or has had breast cancer or a
cancer affecting female reproductive organs, cutaneous system, musculoskeletal system,
soft tissues of the extremities or trunk, male reproductive system, urinary system,
or the head and neck. In some embodiments, the subject has undergone axillary lymph
node dissection. In some embodiments, the subject has received treatment for cancer,
and the edema, lymphedema, or lymphatic injury is associated with the cancer treatment
or diagnosis. For example, the subject may be receiving or may have received chemotherapy
or radiation therapy for cancer treatment or other indications, or may have had one
or more lymph nodes surgically removed in the course of cancer treatment or diagnosis.
[0141] In some embodiments, the subject has sustained a lymphatic injury (for example as
the result of removal, ligation or obstruction of lymph nodes or lymph vessels, or
fibrosis of lymph tissue), or the subject is obese or has or has had an infection
that leads to edema, such as lymphedema. In some embodiments, the infection is a skin
infection or a history of skin infection related to lymphedema or lymphatic injury.
In some embodiments, the infection is a parasitic infection that obstructs lymphatic
flow or injures the lymphatic system. In some embodiments, the subject has sustained
lymphatic injury from joint replacement, trauma, burns, radiation, or chemotherapy.
[0142] In some embodiments, the disclosure provides methods for preventing edema comprising
administering to a subject in need thereof a deuterium-enriched pirfenidone compound
disclosed herein, for example, a compound of Formula I, e.g., a compound listed in
Table 1, including e.g., LYT-100. In some embodiments, the disclosure provides methods
for preventing lymphedema comprising administering to a subject in need thereof a
deuterium-enriched pirfenidone compound disclosed herein, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100. In some
embodiments, the disclosure provides methods for preventing secondary lymphedema comprising
administering to a subject in need thereof a deuterium-enriched pirfenidone compound
disclosed herein, for example, a compound of Formula I, e.g., a compound listed in
Table 1, including e.g., LYT-100. In some embodiments, the disclosure provides methods
for preventing primary lymphedema comprising administering to a subject in need thereof
a deuterium-enriched pirfenidone compound disclosed herein, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100.
[0143] In some embodiments, the lymphedema occurs in one or both arms, such as in the hand,
wrist, forearm, elbow, upper arm, shoulder, armit, or combination of arm areas or
the entire arm. In some embodiments, the lymphedema occurs in one or both legs, such
as in the foot, ankle, leg, knee, upper leg or thigh, groin, hip, or combination of
leg areas or the entire leg. In some embodiments, the lymphedema occurs in the head,
neck, jaw, chest, breast, thorax, abdomen, pelvis, genitals, or other areas of the
body cavity. In some embodiments, the lymphedema occurs in one or more limbs, or in
one or more limbs and another area of the body.
[0144] In some embodiments the lymphedema results from a vascular defect, including venous
insufficiency, venous malformation, arterial malformation, capillary malformation,
lymphovascular malformation, or cardiovascular disease.
[0145] In some embodiments, the disclosure provides methods for amelorating one or more
symptoms of edema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound disclosed herein, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100. In some embodiments, the disclosure
provides methods for amelorating one or more symptoms of lymphedema comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100. In some embodiments, the disclosure provides methods for amelorating
one or more symptoms of secondary lymphedema comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100.
In some embodiments, the disclosure provides methods for amelorating one or more symptoms
of primary lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound disclosed herein, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100.
[0146] In some embodiments, the lymphedema occurs in one or both arms, such as in the hand,
wrist, forearm, elbow, upper arm, shoulder, armit, or combination of arm areas or
the entire arm. In some embodiments, the lymphedema occurs in one or both legs, such
as in the foot, ankle, leg, knee, upper leg or thigh, groin, hip, or combination of
leg areas or the entire leg. In some embodiments, the lymphedema occurs in the head,
neck, jaw, chest, breast, thorax, abdomen, pelvis, genitals, or other areas of the
body cavity. In some embodiments, the lymphedema occurs in one or more limbs, or in
one or more limbs and another area of the body.
[0147] In some embodiments the lymphedema results from a vascular defect, including venous
insufficiency, venous malformation, arterial malformation, capillary malformation,
lymphovascular malformation, or cardiovascular disease.
[0148] In any of the above-described methods for treating, preventing, or ameliorating one
or more symptoms of edema or lymphedema, the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is administered orally twice a day, for a total daily dose of 100-1500
mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700,
750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In
some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is
750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily
dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is administered
orally 750 mg twice daily. In some embodiments, the deuterium-enriched pirfenidone
is administered orally 500 mg twice daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 250 mg twice daily.
[0149] In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100,
is administered orally once a day, for a total daily dose of 100-1500 mg. In some
embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900,
1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments,
the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some
embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250
mg. In some embodiments, the deuterium-enriched pirfenidone is administered orally
1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone is administered
orally 1000 mg once daily. In some embodiments, the deuterium-enriched pirfenidone
is administered orally 750 mg once daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 500 mg once daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 250 mg once daily.
[0150] In any of the above-described embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100 is administered orally three times a day, for a total daily dose of
100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500,
600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is
1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the
daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments,
the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone
is administered orally 500 mg three times daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 333 mg three times daily. In some embodiments,
the deuterium-enriched pirfenidone is administered orally 166 mg three times daily.
[0151] In some embodiments, the deuterium-enriched pirfenidone is in tablet form. In some
embodiments, the deuterium-enriched pirfenidone is taken orally with food.
[0152] Thus, provided herein are methods for the treatment, prevention, and/or amelioration
of edema, e.g.lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including e.g., LYT-100, wherein the deuterium-enriched pirfenidone compound
is administered orally twice a day, for a total daily dose of 100-1500 mg. In some
embodiments, provided herein are methods for the treatment, prevention, and/or amelioration
of edeme, e.g., lymphedema comprising administering to a subject in need thereof LYT-100,
wherein LYT-100 is administered orally twice a day, for a total daily dose of 100-1500
mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100, is 1000 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 750 mg. In some
embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100 is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone
compound, e.g., LYT-100 is 250 mg. In some embodiments, the deuterium-enriched pirfenidone
compound, e.g., LYT-100 is administered orally 750 mg twice daily. In some embodiments,
the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally
500 mg twice daily. In some embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is administered orally 250 mg twice daily.
[0153] In some embodiments, provided herein are methods for the treatment, prevention, and/or
amelioration of edema, e.g., lymphedema comprising administering to a subject in need
thereof a deuterirum-enriched pirfenidone compound, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, wherein the deuterirum-enriched
pirfenidone compound is administered orally once a day, for a total daily dose of
100-1500 mg. In some embodiments, provided herein are methods for the treatment, prevention,
and/or amelioration of edema, e.g., lymphedema comprising administering to a subject
in need thereof LYT-100, wherein LYT-100, is administered orally once a day, for a
total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100 is 1500 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1000 mg. In some
embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100 is 500 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 250 mg. In some
embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered
orally 1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone
compound, e.g., LYT-100, is administered orally 1000 mg once daily. In some embodiments,
the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally
750 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is administered orally 500 mg once daily. In some embodiments, the
deuterium-enriched pirfenidone compound, e.g., LYT-100 is administered orally 250
mg once daily.
[0154] Thus, provided herein are methods for the treatment, prevention, and/or amelioration
of edema, e.g., lymphedema comprising administering to a subject in need thereof a
deuterium-enriched pirfenidone compound, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, wherein the deuterium-enriched
pirfenidone compound is administered orally three times daily, for a total daily dose
of 100-1500 mg. In some embodiments, provided herein are methods for the treatment,
prevention, and/or amelioration of edema, e.g., lymphedema comprising administering
to a subject in need thereof LYT-100, wherein LYT-100 is administered orally three
times a day, for a total daily dose of 100-1500 mg. In some embodiments, the daily
dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In
some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100, is 750 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100 is 500 mg. In some embodiments,
the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100 is 250
mg. In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100
is administered orally 500 mg three times daily. In some embodiments, the deuterium-enriched
pirfenidone compound, e.g., LYT-100, is administered orally 333 mg three timese daily.
In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is
administered orally 166 mg twice daily.
[0155] In other embodiments, the deuterium-enriched pirfenidone compound is administered
orally at a total daily dose of 100-2500 mg. In some embodiments, the deuterium-enriched
pirfenidone compound is administered orally at a total daily dose of 100-2000 mg.
In some embodiments, the deuterium-enriched pirfenidone compound is administered orally
at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-enriched
pirfenidone compound is administered orally at a total daily dose of 100-1000 mg.
In some embodiments, the deuterium-enriched pirfenidone compound is administered orally
at a total daily dose of 100-500 mg. In some embodiments, the daily dose is selected
from 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300,
1400, 1500, 1600, 1700,1800, 1900, 2000, 2100, 2200, 2300, 2400, and 2500 mg/day.
In some embodiments, the deuterium-enriched pirfenidone compound is administered orally
three times/day (TID). In some embodiments, the deuterium-enriched pirfenidone compound
is administered orally two times/day (BID). In some embodiments, the deuterium-enriched
pirfenidone compound is administered orally once daily (QD). In any of these embodiments,
the deuterium-enriched pirfenidone compound has the structure of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100.
[0156] In some embodiments, the disclosure provides methods for treating edema, e.g., lymphedema,
comprising administering to a subject in need thereof a deuterium-enriched pirfenidone
compound disclosed herein, for example, a compound of Formula I, e.g., a compound
listed in Table 1, including e.g., LYT-100. In some embodiments, the method comprises
administering an effective amount of deuterium-enriched pirfenidone, e.g., the deuterated
pirfenidone compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein edema, e.g., lymphedema, is
treated in the subj ect.
[0157] In some embodiments the lymphedema is secondary lymphedema. Secondary lymphedema
can develop after surgery, infection or trauma, and is frequently caused by cancer,
cancer treatments such as surgery, biopsy, radiation and chemotherapy, trauma or infections
resulting in damage to or the removal of lymph nodes. Accordingly, in some embodiments,
the disclosure provides a method for treating edema comprising administering to a
subject in need thereof a deuterated pirfenidone compound having the structure:

[0158] In some embodiments, the disclosure provides a method for treating lymphedema comprising
administering to a subject in need thereof a deuterated pirfenidone compound having
the structure:

[0159] In some embodiments, the disclosure provides a method for treating secondary lymphedema
comprising administering to a subject in need thereof a deuterated pirfenidone compound
having the structure:

[0160] In some embodiments, the disclosure provides a method for treating primary lymphedema
comprising administering to a subject in need thereof a deuterated pirfenidone compound
having the structure:

[0161] In some embodiments, the disclosure provides methods for preventing edema, e.g.,
lymphedema, comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound disclosed herein, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100. In some embodiments, the method
comprises administering an effective amount of deuterium-enriched pirfenidone, e.g.,
the deuterated pirfenidone compound having the structure:

[0162] or a pharmaceutically acceptable salt thereof, wherein edema, e.g., lymphedema, is
prevented in the subject. In some embodiments the lymphedema is secondary lymphedema.
Secondary lymphedema can develop after surgery, infection or trauma, and is frequently
caused by cancer, cancer treatments such as surgery, biopsy, radiation and chemotherapy,
trauma or infections resulting in damage to or the removal of lymph nodes. Accordingly,
in some embodiments, the disclosure provides a method for preventing edema comprising
administering to a subject in need thereof a deuterated pirfenidone compound having
the structure:

[0163] In some embodiments, the disclosure provides a method for preventing lymphedema comprising
administering to a subject in need thereof a deuterated pirfenidone compound having
the structure:

[0164] In some embodiments, the disclosure provides a method for preventing secondary lymphedema
comprising administering to a subject in need thereof a deuterated pirfenidone compound
having the structure:

[0165] In some embodiments, the disclosure provides a method for preventing primary lymphedema
comprising administering to a subject in need thereof a deuterated pirfenidone compound
having the structure:

[0166] In some embodiments, the disclosure provides methods for ameliorating one or more
symptoms of edema, e.g., lymphedema, comprising administering to a subject in need
thereof a deuterium-enriched pirfenidone compound disclosed herein, for example, a
compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100.
In some embodiments, the method comprises administering an effective amount of deuterium-enriched
pirfenidone, e.g., the deuterated pirfenidone compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein one or more symptoms of the
edema, e.g., lymphedema, is ameliorated in the subject. In some embodiments the lymphedema
is secondary lymphedema. Secondary lymphedema can develop after surgery, infection
or trauma, and is frequently caused by cancer, cancer treatments such as radiation
and chemotherapy, trauma or infections resulting in damage to or the removal of lymph
nodes. Accordingly, in some embodiments, the disclosure provides a method for ameliorating
one or more symptoms of edema comprising administering to a subject in need thereof
a deuterated pirfenidone compound having the structure:

[0167] In some embodiments, the disclosure provides a method for ameliorating one or more
symptoms of lymphedema comprising administering to a subject in need thereof a deuterated
pirfenidone compound having the structure:

[0168] In some embodiments, the disclosure provides a method for ameliorating one or more
symptoms of secondary lymphedema comprising administering to a subject in need thereof
a deuterated pirfenidone compound having the structure:

[0169] In some embodiments, the disclosure provides a method for ameliorating one or more
symptoms of primary lymphedema comprising administering to a subject in need thereof
a deuterated pirfenidone compound having the structure:

[0170] In any of the above embodiments, the one or more symptom(s) ameliorated is selected
from: accumulation of fluid beneath the skin and in body cavities, swelling, fullness,
swelling or puffiness of tissues, inflammation, fibrosis, heaviness, pain, disfigurement,
decreased range of motion, aching, recurring infections, skin thickening, and discomfort.
[0171] In any of these embodiments for treating various forms of lymphedema, the lymphedema
may occur in one or both arms, such as in the hand, wrist, forearm, elbow, upper arm,
shoulder, armit, or combination of arm areas or the entire arm. In some embodiments,
the lymphedema occurs in one or both legs, such as in the foot, ankle, leg, knee,
upper leg or thigh, groin, hip, or combination of leg areas or the entire leg. In
some embodiments, the lymphedema occurs in the head, neck, jaw, chest, breast, thorax,
abdomen, pelvis, genitals, or other areas of the body cavity. In some embodiments,
the lymphedema occurs in one or more limbs, or in one or more limbs and another area
of the body.
[0172] In any of these embodiments for treating lymphedema the lymphedema may result from
a vascular defect, including venous insufficiency, venous malformation, arterial malformation,
capillary malformation, lymphovascular malformation, or cardiovascular disease.
[0173] Cellulitis is a serious, potentially life-threatening infection that can affect patients
with lymphedema. Cellulitis can increase inflammation and further worsen lymphedema.
Patients with lymphedema can have recurrent and progressive episodes of cellulitis
requiring intravenous antibiotics. Prophylactic antibiotics are the only available
intervention for trying to reduce cellulitis. In some embodiments, provided herein
are methods for reducing cellulitis in a subject comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100.
In some embodiments, episodes of cellulitis are reduced by at least 5%, 10%, 15%,
20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, the severity of the
infection is decreased from severe to moderate or moderate to mild. In some embodiments,
the use of treatment-related or prophylactic antibiotics is reduced.
[0174] In any of the above-described methods for treating, preventing, or ameliorating one
or more symptoms of edema or lymphedema, the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is administered orally twice a day, for a total daily dose of 100-1500
mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700,
750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In
some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is
750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily
dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is administered
orally 750 mg twice daily. In some embodiments, the deuterium-enriched pirfenidone
is administered orally 500 mg twice daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 250 mg twice daily.
[0175] In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100,
is administered orally once a day, for a total daily dose of 100-1500 mg. In some
embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900,
1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments,
the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some
embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250
mg. In some embodiments, the deuterium-enriched pirfenidone is administered orally
1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone is administered
orally 1000 mg once daily. In some embodiments, the deuterium-enriched pirfenidone
is administered orally 750 mg once daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 500 mg once daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 250 mg once daily.
[0176] In any of the above-described embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100 is administered orally three times a day, for a total daily dose of
100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500,
600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is
1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the
daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments,
the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone
is administered orally 500 mg three times daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 333 mg three times daily. In some embodiments,
the deuterium-enriched pirfenidone is administered orally 166 mg three times daily.
[0177] In some embodiments, the deuterium-enriched pirfenidone is in tablet form. In some
embodiments, the deuterium-enriched pirfenidone is taken orally with food.
[0178] Thus, provided herein are methods for the treatment, prevention, and/or amelioration
of edema, e.g.lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including e.g., LYT-100, wherein the deuterium-enriched pirfenidone compound
is administered orally twice a day, for a total daily dose of 100-1500 mg. In some
embodiments, provided herein are methods for the treatment, prevention, and/or amelioration
of edeme, e.g., lymphedema comprising administering to a subject in need thereof LYT-100,
wherein LYT-100 is administered orally twice a day, for a total daily dose of 100-1500
mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100, is 1000 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 750 mg. In some
embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100 is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone
compound, e.g., LYT-100 is 250 mg. In some embodiments, the deuterium-enriched pirfenidone
compound, e.g., LYT-100 is administered orally 750 mg twice daily. In some embodiments,
the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally
500 mg twice daily. In some embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is administered orally 250 mg twice daily.
[0179] In some embodiments, provided herein are methods for the treatment, prevention, and/or
amelioration of edema, e.g., lymphedema comprising administering to a subject in need
thereof a deuterirum-enriched pirfenidone compound, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, wherein the deuterirum-enriched
pirfenidone compound is administered orally once a day, for a total daily dose of
100-1500 mg. In some embodiments, provided herein are methods for the treatment, prevention,
and/or amelioration of edema, e.g., lymphedema comprising administering to a subject
in need thereof LYT-100, wherein LYT-100, is administered orally once a day, for a
total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100 is 1500 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1000 mg. In some
embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100 is 500 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 250 mg. In some
embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered
orally 1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone
compound, e.g., LYT-100, is administered orally 1000 mg once daily. In some embodiments,
the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally
750 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is administered orally 500 mg once daily. In some embodiments, the
deuterium-enriched pirfenidone compound, e.g., LYT-100 is administered orally 250
mg once daily.
[0180] Thus, provided herein are methods for the treatment, prevention, and/or amelioration
of edema, e.g., lymphedema comprising administering to a subject in need thereof a
deuterium-enriched pirfenidone compound, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, wherein the deuterium-enriched
pirfenidone compound is administered orally three times daily, for a total daily dose
of 100-1500 mg. In some embodiments, provided herein are methods for the treatment,
prevention, and/or amelioration of edema, e.g., lymphedema comprising administering
to a subject in need thereof LYT-100, wherein LYT-100 is administered orally three
times a day, for a total daily dose of 100-1500 mg. In some embodiments, the daily
dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In
some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100, is 750 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100 is 500 mg. In some embodiments,
the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100 is 250
mg. In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100
is administered orally 500 mg three times daily. In some embodiments, the deuterium-enriched
pirfenidone compound, e.g., LYT-100, is administered orally 333 mg three timese daily.
In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is
administered orally 166 mg twice daily.
[0181] In other embodiments, the deuterium-enriched pirfenidone compound is administered
orally at a total daily dose of 100-2500 mg. In some embodiments, the deuterium-enriched
pirfenidone compound is administered orally at a total daily dose of 100-2000 mg.
In some embodiments, the deuterium-enriched pirfenidone compound is administered orally
at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-enriched
pirfenidone compound is administered orally at a total daily dose of 100-1000 mg.
In some embodiments, the deuterium-enriched pirfenidone compound is administered orally
at a total daily dose of 100-500 mg. In some embodiments, the daily dose is selected
from 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300,
1400, 1500, 1600, 1700,1800, 1900, 2000, 2100, 2200, 2300, 2400, and 2500 mg/day.
In some embodiments, the deuterium-enriched pirfenidone compound is administered orally
three times/day (TID). In some embodiments, the deuterium-enriched pirfenidone compound
is administered orally two times/day (BID). In some embodiments, the deuterium-enriched
pirfenidone compound is administered orally once daily (QD). In any of these embodiments,
the deuterium-enriched pirfenidone compound has the structure of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100.
[0182] Lymphedema typically progresses through multiple stages, with increased fibrosis,
limb volume and tissue changes. Of more than 250,000 Americans estimated to be diagnosed
with breast cancer each year that undergo surgery, up to one in five will develop
secondary lymphedema. Beyond breast cancer, lymphedema can occur in up to 15 percent
of cancer survivors with malignancies ranging from melanoma and sarcoma. A subset
of lymphedema patients will also experience cellulitis, a bacterial skin infection
that can enter through wounds in lymphedematous skin. Cellulitis often requires hospitalization
and intravenous antibiotics to treat, and approximately half of patients with cellulitis
will have recurrent episodes. In some rare instances, patients with chronic lymphedema
may develop lymphangiosarcoma, a malignant tumor. Lymphedema is classified by clinical
staging and severity, as shown in the table below.
Table 2: Clinical Stages of Lymphedema |
|
Stage I |
Stage II |
Stage III |
Symptoms |
Limb swelling, pitting edema, limb heaviness and discomfort |
Limb swelling, skin thickening, dermal fibrosis, fat deposition, non-pitting edema |
Disfiguring limb swelling, hyperkeratosis, loss of skin elasticity, skin lesions and
overgrowths, massive fibrosis and fat deposition, elephantiasis |
Additional Clinical Concerns |
Lifelong need for compression therapy, chronic progression, repeated infections (cellulitis,
lymphangitis), elephantine skin changes, development of lymphangiosarcoma |
[0183] In some embodiments, the subject or patient has Stage I lymphedema. In some embodiments,
the subject or patient has Stage II lymphedema. In some embodiments, the subject or
patient has Stage III lymphedema. In some embodiments, the subject or patient is reduced
in stage from Stage III to Stage II or Stage I, or from Stage II to Stage I.
[0184] The International Society of Lymphology classifies a lymphedematous limb based on
staging that describes the condition of the limb. As the disease progresses into later
stages, the affected limb can acquire a "woody texture" due to fibrosis. In addition
to clinical staging, clinicians use a measurement of limb swelling to capture disease
severity. Cancer treatments lead to new lymphedema patients each year, the majority
of which will have mild lymphedema: over 70 percent of patients with secondary lymphedema
have milder forms of lymphedema, while the remainder have moderate to severe lymphedema.
The table below summarizes the percentage of secondary breast cancer-related lymphedema
patients who experience various stages of severity of lymphedema.
Table 3: Severity of Secondary Lymphedema |
|
Mild |
Moderate |
Severe |
Relative Limb Volume Change |
5-20% |
20-40% |
>40% |
Percentage Patients |
73% |
27% |
[0185] Accordingly, in some embodiments, patients have mild, moderate or severe secondary
lymphedema. In some embodiments, patients have mild to moderate secondary lymphedema.
In some embodiments, patient have moderate to severe secondary lymphedema. In some
embodiments, patients have mild to severe secondary lymphedema.
[0186] The natural history of lymphedema is a chronic and progressive disorder, reflected
in the increasing severity of limb swelling. The relative increase of limb volume
in the affected limb compared to the unaffected limb worsens over time. In patients
with mild lymphedema, approximately 48 percent will progress to more severe stages
during the first five years of follow-up. Because of the progressive nature of the
disease, many patients will progress to the point where bandaging and compression
are incapable of reducing limb volume. The potential loss of limb range of motion
and function, the risk of secondary infections and complications and the disfigurement
result in physical and emotional suffering in cancer survivors. Secondary lymphedema
is a lifelong disease and the affected population is increasing each year due to improved
survival of cancer patients, changes in patient and disease factors, including obesity,
an aging population and increased use of radiation treatment.
[0187] Millions of patients have lymphedema beyond breast cancer-related arm lymphedema.
The deuterium-enriched pirfenidone compounds disclosed here, e.g., LYT-100 can be
used to treat the underlying mechanisms of other forms of secondary or primary lymphedema,
for example, lymphatic filariasis.
[0188] The deuterium-enriched pirfenidone compounds disclosed here, e.g., LYT-100 can be
used to treat various forms of lymphedema. In some embodiments, the lymphedema to
be treated occurs in one or both arms, such as in the hand, wrist, forearm, elbow,
upper arm, shoulder, armit, or combination of arm areas or the entire arm. In some
embodiments, the lymphedema occurs in one or both legs, such as in the foot, ankle,
leg, knee, upper leg or thigh, groin, hip, or combination of leg areas or the entire
leg. In some embodiments, the lymphedema occurs in the head, neck, jaw, chest, breast,
thorax, abdomen, pelvis, genitals, or other areas of the body cavity. In some embodiments,
the lymphedema occurs in one or more limbs, or in one or more limbs and another area
of the body.
[0189] In any of these embodiments for treating lymphedema the lymphedema may result from
a vascular defect, including venous insufficiency, venous malformation, arterial malformation,
capillary malformation, lymphovascular malformation, or cardiovascular disease.
[0190] The deuterium-enriched pirfenidone compounds disclosed here, e.g., LYT-100 can be
used to treat cellulitis, which is a serious, potentially life-threatening infection
that can affect patients with lymphedema. In some embodiments, provided herein are
methods for reducing cellulitis in a subject comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100.
[0191] In some embodiments, the patients have had breast cancer surgery at least 3, 6, 9,
or 12 months prior, and who have completed radiation treatment due to breast cancer
at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve
months prior. In some embodiment, they are without recurrent cancer more than 6 months
after the breast cancer surgery. In some embodiments, patients are those having pitting
edema and at least one of the following: increase in relative limb volume of between
10-20% as measured by the truncated cone method of circumferential tape measurement,
or a bioimpedance measure of > +6.5 L-Dex. In some embodiments, patients are also
on standard of care compression or have a relative limb volume > 10% or L-Dex > 14
as compared to pre-surgery and/or pre-radiation volumes. Thus, in some embodiments,
the disclosure provides a method for treating lymphedema comprising administering
to a subject in need thereof LYT-100, wherein the subject has an increase in relative
limb volume of at least 10% as compared to pre-treatment limb volumes. Thus, in some
embodiments, the disclosure provides a method for treating lymphedema comprising administering
to a subject in need thereof LYT-100, wherein the subject has an increase in relative
limb volume of between 10-20% as compared to pre-treatment limb volumes. In some embodiments,
the disclosure provides a method for treating lymphedema comprising administering
to a subject in need thereof LYT-100, wherein the subject has an increase in relative
limb volume of greater than 20% as compared to pre-treatment limb volumes. In some
embodiments, the disclosure provides a method for treating lymphedema comprising administering
to a subject in need thereof LYT-100, wherein the subject has an increase in relative
limb volume of between 20% - 40% as compared to pre-treatment limb volumes. In some
embodiments, the disclosure provides a method for treating lymphedema comprising administering
to a subject in need thereof LYT-100, wherein the subject has an increase in relative
limb volume of greater than 40% as compared to pre-treatment limb volumes. In some
embodiments, the disclosure provides a method for treating lymphedema comprising administering
to a subject in need thereof LYT-100, wherein the subject has a bioimpedance measure
of at least +6.5 L-Dex as compared with pre-treatment limb volumes. In some embodiments,
the disclosure provides a method for treating lymphedema comprising administering
to a subject in need thereof LYT-100, wherein the subject has a bioimpedance measure
of at least +14 L-Dex as compared with pre-treatment limb volumes.
[0192] In some embodiments, the disclosure provides a method for treating edema, e.g., lymphedema
comprising administering to a subject in need thereof a deuterium-enriched pirfenidone
compound, e.g., a compound of Formula 1, including those compounds listed in Table
1, wherein treatment is demonstrated by the subject having an improvement in one or
more of the measurements selected from: a) bioimpedance (as measured, e.g., by BIS),
b) limb volume (as measured, e.g., by a perometer or tape measure), c) local tissue
water content (as measured, e.g., by the tissue dielectric constant), d) tissue firmness
(as measured, e.g., by tonometric device), e) fibrosis (e.g., as measured by tissue
firmness), f) pain, g) swelling, h) discomfort, i) function, j) visual-analog pain
score, h) Upper Limb Lymphedema Score (ULL27), i) Lymphema Life Impact Scale (LLIS),
j) Functional Assessment of Cancer Therapy score (FACT-B+4), k) Lymphedema Quality
of Life score (LYMQOL); 1) Disabilities of the Arm, Shoulder, and Hand score (DASH);
m) Lymphedema Quality of Life Inventory (LQOLI), n) Granulocyte Colony Stimulating
Factor (G-CSF), o) cutaneous histological architecture (CHA); and p) skin thckness
(as measured, e.g., by calipers).
[0193] In some embodiments, the disclosure provides a method for ameliorating one or more
symptoms of edema, e.g., lymphedema comprising administering to a subject in need
thereof LYT-100, wherein amelioration of one or more symptoms is demonstrated by the
subject having an improvement in one or more of the measurements selected from: a)
bioimpedance (as measured, e.g., by BIS), b) limb volume (as measured, e.g., by a
perometer or tape measure), c) local tissue water content (as measured, e.g., by the
tissue dielectric constant), d) tissue firmness (as measured, e.g., by tonometric
device), e) fibrosis (e.g., as measured by tissue firmness), f) pain, g) swelling,
h) discomfort, i) function, j) visual-analog pain score, h) Upper Limb Lymphedema
Score (ULL27), i) Lymphema Life Impact Scale (LLIS), j) Functional Assessment of Cancer
Therapy score (FACT-B+4), k) Lymphedema Quality of Life score (LYMQOL); 1) Disabilities
of the Arm, Shoulder, and Hand score (DASH); m) Lymphedema Quality of Life Inventory
(LQOLI), n) Granulocyte Colony Stimulating Factor (G-CSF), o) cutaneous histological
architecture (CHA); and p) skin thckness (as measured, e.g., by calipers).
[0194] Bioimpedance, or water content, can be measured via Bioelectrical impedance spectroscopy
(BIS). Multiple frequency bioelectrical impedance spectroscopy (BIS) provides accurate
relative measures of protein-rich fluid in the upper limb of patients. BIS is a noninvasive
technique that involves passing an extremely small electrical current through the
body and measuring the impedance (or resistance) to the flow of this current. The
electrical current is primarily conducted by the water containing fluids in the body.
BIS quantifies the amount of protein-rich fluid in lymphedema by comparison of the
affected and non-affected limbs. In some embodiments, the disclosure provides methods
for decreasing bioimpedance in the limb of a subject comprising administering to the
subject a deuterium-enriched pirfenidone compound disclosed herein, for example, a
compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the
deuterium-enriched pirfenidone compound is LYT-100. Thus, in some embodiments, the
disclosure provides methods for decreasing bioimpedance in a subject with edema, e.g.,lymphedema,
comprising administering an effective amount of LYT-100. In some embodiments, provided
herein are methods for treating lymphedema comprising administering to a subject having
lymphedema in at least one limb a deuterium-enriched pirfenidone compound, e.g., LYT-100,
wherein the bioimpedance in the subject's limb is decreased as compared to the bioimpedance
in the subject's limb prior to the administration of the deuterium-enriched pirfenidone
compound, e.g., LYT-100. In some embodiments, bioimpedance is significantly decreased
by 3, 4 or 6 months. In some embodiments of the disclosed methods, bioimpedance is
decreased by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,
50% (and any numerical increment between), or more as compared to bioimpedance in
the subject's limb prior to the administration of the deuterium-enriched pirfenidone
compound. This decrease is seen in 3, 4, or 6 months in some embodiments. Thus, in
some embodiments, the disclosure provides a method for decreasing bioimpedance in
the limb of a subject comprising administering to the subject LYT-100, wherein the
bioimpedance is decreased. In some embodiments, the disclosure provides a method for
decreasing bioimpedance in the limb of a subject comprising administering to the subject
LYT-100, wherein the bioimpedance is decreased as compared to bioimpedance in the
subject's limb prior to the administration of LYT-100. In some embodiments, the disclosure
provides a method for decreasing bioimpedance in the limb of a subject comprising
administering to the subject LYT-100, wherein the bioimpedance is decreased by at
least 2% as compared to bioimpedance in the subject's limb prior to the administration
of LYT-100. In some embodiments, the disclosure provides a method for decreasing bioimpedance
in the limb of a subject comprising administering to the subject LYT-100, wherein
the bioimpedance is decreased by at least 3%, at least 4%, at least 5%, at least 6%,
at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at
least 13%, at least 14% at least 15%, at least 16%, at least 17%, at least 18%, at
least 19%, or at least 20% as compared to bioimpedance in the subject's limb prior
to the administration of LYT-100. In some embodiments, the disclosure provides a method
for decreasing bioimpedance in the limb of a subject comprising administering to the
subject LYT-100, wherein the bioimpedance is decreased by greater than 20% as compared
to bioimpedance in the subject's limb prior to the administration of LYT-100.
[0195] Limb Volume (Perometry). Relative limb volume can be measured by the truncated cone
method of circumferential tape measurement. Perometry is a noninvasive technique involving
a Perometer (Pero-System), which uses infrared light to scan a limb and obtain measurements
of the limb's circumference. In some embodiments, the disclosure provides methods
for reducing (decreasing) limb volume in the limb of a subject comprising administering
to the subject a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments,
the deuterium-enriched pirfenidone compound is LYT-100. Thus, in some embodiments,
the disclosure provides methods for decreasing limb volume in a subject with edema,
e.g., lymphedema, comprising administering an effective amount of LYT-100. In some
embodiments, provided herein are methods for treating lymphedema comprising administering
to a subject having lymphedema in at least one limb a deuterium-enriched pirfenidone
compound, e.g., LYT-100, wherein the limb volume in the subject's limb is decreased
as compared to the limb volume in the subject's limb prior to the administration of
the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, limb
volume is decreased by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%,
30%, 35%, 40%, 45%, 50%, or more as compared to limb volume in the subject's limb
prior to administration of the deuterium-enriched pirfenidone. In some embodiments,
the severity is decreased from severe to moderate or moderate to mild. In some embodiments,
this decrease in limb volume is seen in 3, 4, or 6 months. Thus, in some embodiments,
the disclosure provides a method for decreasing limb volume in the limb of a subject
comprising administering to the subject LYT-100, wherein the limb volume is decreased.
In some embodiments, the disclosure provides a method for decreasing limb volume in
the limb of a subject comprising administering to the subject LYT-100, wherein the
limb volume is decreased as compared to limb volume in the subject's limb prior to
the administration of LYT-100. In some embodiments, the disclosure provides a method
for decreasing limb volume in the limb of a subject comprising administering to the
subject LYT-100, wherein the limb volume is decreased by at least 2% as compared to
limb volume in the subject's limb prior to the administration of LYT-100. In some
embodiments, the disclosure provides a method for decreasing limb volume in the limb
of a subject comprising administering to the subject LYT-100, wherein the limb volume
is decreased by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at
least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at
least 14% at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or
at least 20% as compared to limb volume in the subject's limb prior to the administration
of LYT-100. In some embodiments, the disclosure provides a method for decreasing limb
volume in the limb of a subject comprising administering to the subject LYT-100, wherein
the limb volume is decreased by greater than 20% as compared to limb volume in the
subject's limb prior to the administration of LYT-100. In some embodiments, the disclosure
provides a method for decreasing limb volume in the limb of a subject comprising administering
to the subject LYT-100, wherein the limb volume is decreased by 20% - 40% as compared
to limb volume in the subject's limb prior to the administration of LYT-100. In some
embodiments, the disclosure provides a method for decreasing limb volume in the limb
of a subject comprising administering to the subject LYT-100, wherein the limb volume
is decreased by greater than 40% as compared to limb volume in the subject's limb
prior to the administration of LYT-100.
[0196] Tissue Dielectric Constant (MoistureMeterD). The tissue dielectric constant measures
the local tissue water content under the skin at various depths ranging from skin
to subcutis. The results are converted into a 0-100% scale to reflect subcutaneous
fluid deposition that can occur in early stage lymphedema. In some embodiments, the
disclosure provides methods for decreasing the tissue dielectric constant in a subject
comprising administering to the subject a deuterium-enriched pirfenidone compound
disclosed herein, for example, a compound of Formula I, e.g., a compound listed in
Table 1. In some embodiments, the deuterium-enriched pirfenidone compound is LYT-100.
In some embodiments, provided herein are methods for treating lymphedema comprising
administering to a subject having lymphedema in at least one limb a deuterium-enriched
pirfenidone compound, e.g., LYT-100, wherein the tissue dielectric constant in the
subject's limb is decreased as compared to the tissue dielectric constant in the subject's
limb prior to the administration of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100. Thus, in some embodiments, the disclosure provides methods for decreasing
the tisssue dielectric constant in the limb of a subject with edema, e.g., lymphedema,
comprising administering an effective amount of LYT-100. In some embodiments, the
tissue dielectric constant is decreased by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%,
20%, 25%, 30%, 35%, 40%, 45%, 50%, or more as compared to the tissue dielectric constant
in the subject's limb prior to administration of the deuterium-enriched pirfenidone.
In some embodiments, the disclosure provides a method for decreasing the tissue dielectric
constant in the limb of a subject comprising administering to the subject LYT-100,
wherein the tissue dielectric constant is decreased. In some embodiments, the disclosure
provides a method for decreasing the tissue dielectric constant in the limb of a subject
comprising administering to the subject LYT-100, wherein the tissue dielectric constant
is decreased as compared to the tissue dielectric constant in the subject's limb prior
to the administration of LYT-100. In some embodiments, the disclosure provides a method
for decreasing the tissue dielectric constant in the limb of a subject comprising
administering to the subject LYT-100, wherein the tissue dielectric constant is decreased
by at least 2% as compared to the tissue dielectric constant in the subject's limb
prior to the administration of LYT-100. In some embodiments, the disclosure provides
a method for decreasing the tissue dielectric constant in the limb of a subject comprising
administering to the subject LYT-100, wherein the tissue dielectric constant is decreased
by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at
least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14% at
least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20%
as compared to the tissue dielectric constant in the subject's limb prior to the administration
of LYT-100. In some embodiments, the disclosure provides a method for decreasing the
tissue dielectric constant in the limb of a subject comprising administering to the
subject LYT-100, wherein the tissue dielectric constant is decreased by greater than
20% as compared to the tissue dielectric constant in the subject's limb prior to the
administration of LYT-100.
[0197] Tissue Firmness (Tonometry/SkinFibroMeter). A tonometer device is pressed into the
skin to measure the amount of force required to make an indent in the tissue. The
resulting measurement gauges the degree of firmness or fibrosis (tissue scarring)
under the skin to assess the severity of lymphedema. In some embodiments, the disclosure
provides methods for decreasing tissue firmness in the limb of a subject comprising
administering to the subject a deuterium-enriched pirfenidone compound disclosed herein,
for example, a compound of Formula I, e.g., a compound listed in Table 1. In some
embodiments, the deuterium-enriched pirfenidone is LYT-100. Thus, in some embodiments,
the disclosure provides methods for decreasing tissue firmness in the limb of a subject
with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100.
In some embodiments, provided herein are methods for treating lymphedema comprising
administering to a subject having lymphedema in at least one limb a deuterium-enriched
pirfenidone compound, e.g., LYT-100, wherein the tissue firmness in the subject's
limb is decreased as compared to the tissue firmness in the subject's limb prior to
the administration of deuterium-enriched pirfenidone compound, e.g., LYT-100. In some
embodiments, tissue firmness is decreased by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more as compared to the tissue firmness
in the subject's limb prior to the administration of the deuterium-enriched pirfenidone
compound. In some embodiments, the disclosure provides a method for decreasing the
tissue firmness in the limb of a subject comprising administering to the subject LYT-100,
wherein the tissue firmness is decreased. In some embodiments, the disclosure provides
a method for decreasing the tissue firmness in the limb of a subject comprising administering
to the subject LYT-100, wherein the tissue firmness is decreased as compared to the
tissue firmness in the subject's limb prior to the administration of LYT-100. In some
embodiments, the disclosure provides a method for decreasing the tissue firmness in
the limb of a subject comprising administering to the subject LYT-100, wherein the
tissue firmness is decreased by at least 2% as compared to the tissue firmness in
the subject's limb prior to the administration of LYT-100. In some embodiments, the
disclosure provides a method for decreasing the tissue firmness in the limb of a subject
comprising administering to the subject LYT-100, wherein the tissue firmness is decreased
by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at
least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14% at
least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20%
as compared to the tissue firmness in the subject's limb prior to the administration
of LYT-100. In some embodiments, the disclosure provides a method for decreasing the
tissue firmness in the limb of a subject comprising administering to the subject LYT-100,
wherein the tissue firmness is decreased by greater than 20% as compared to the tissue
firmness in the subject's limb prior to the administration of LYT-100.
[0198] Visual-analogue scales for pain, swelling, discomfort, and function. This graphic
scale has a straight line with endpoints from 0 to 10 that is marked by the patient
to correlate to their extreme limits of pain, swelling, discomfort and function, ranging
from "not at all" to "as bad as it could be." The higher marks on the line indicates
the worse condition. In some embodiments, the disclosure provides methods for reducing
one or more visual-analog pain scores in a subject comprising administering to the
subject a deuterium-enriched pirfenidone compound disclosed herein, for example, a
compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the
deuterium-enriched pirfenidone compound is LYT-100. Thus, in some embodiments, the
disclosure provides methods for reducing one or more visual-analog pain scores in
a subject with edema, e.g., lymphedema, comprising administering an effective amount
of LYT-100. In some embodiments, provided herein are methods for treating lymphedema
comprising administering to a subject having lymphedema a deuterium-enriched pirfenidone
compound, e.g., LYT-100, wherein one or more of the subject's visual-analog pain score(s)
is decreased as compared to the subject's visual-analog pain score(s) prior to the
administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some
embodiments, one or more visual-analog pain score(s) is decreased by 2%, 3%, 4%, 5%,
6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more as compared to
the corresponding visual-analog pain score(s) in the subject prior to the administration
of the deuterium-enriched pirfenidone compound. In some embodiments, the disclosure
provides a method for decreasing one or more visual-analog pain score(s) in a subject
comprising administering to the subject LYT-100, wherein the one or more visual-analog
pain score(s) is decreased. In some embodiments, the disclosure provides a method
for decreasing one or more visual-analog pain score(s) in a subject comprising administering
to the subject LYT-100, wherein the one or more visual-analog pain score(s) is decreased
as compared to the one or more visual-analog pain score(s) in the subject prior to
the administration of LYT-100. In some embodiments, the disclosure provides a method
for decreasing one or more visual-analog pain score(s) in a subject comprising administering
to the subject LYT-100, wherein the one or more visual-analog pain score(s) is decreased
by at least 2% as compared to the one or more visual-analog pain score(s) in the subject
prior to the administration of LYT-100. In some embodiments, the disclosure provides
a method for decreasing one or more visual-analog pain score(s) in a subject comprising
administering to the subject LYT-100, wherein the one or more visual-analog pain score(s)
is decreased by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at
least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at
least 14% at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or
at least 20% as compared to the one or more visual-analog pain score(s) in the subject
prior to the administration of LYT-100. In some embodiments, the disclosure provides
a method for decreasing one or more visual-analog pain score(s) in a subject comprising
administering to the subject LYT-100, wherein the one or more visual-analog pain score(s)
is decreased by greater than 20% as compared to the one or more visual-analog pain
score(s) in the subject prior to the administration of LYT-100.
[0199] Upper Limb Lymphedema Score 27 (ULL27) is a self-report tool consisting of 27 questions
to evaluate arm lymphedema and associated symptoms in breast cancer survivors. Responses
are given on a 5-point Likert scale ranging from "never" to "always." At least the
following domains are addressed: physical (15 items), psychological (7 items) and
social (5 items), with scores ranging from 0 to 100 (100 being the highest score possible).
Lower scores indicate a higher quality of life. In some embodiments, the disclosure
provides methods for decreasing the ULL27 in a subject comprising administering to
the subject a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments,
the deuterium-enriched pirfenidone is LYT-100. Thus, in some embodiments, the disclosure
provides methods for decreasing the ULL27 in a subject with edema, e.g., lymphedema,
comprising administering an effective amount of LYT-100. In some embodiments, provided
herein are methods for treating lymphedema comprising administering to a subject having
lymphedema in at least one limb a deuterium-enriched pirfenidone compound, e.g., LYT-100,
wherein the subject's ULL27 score is decreased as compared to the subject's ULL27
score prior to the administration of the deuterium-enriched pirfenidone compound,
e.g., LYT-100. In some embodiments, the ULL27 is decreased by 2%, 3%, 4%, 5%, 6%,
7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more as compared to the
ULL27 in the subject prior to administration of the deuterium-enriched pirfenidone
compound. In some embodiments, the disclosure provides a method for decreasing the
ULL27 in a subject comprising administering to the subject LYT-100, wherein the ULL27
is decreased. In some embodiments, the disclosure provides a method for decreasing
the ULL27 in a subject comprising administering to the subject LYT-100, wherein the
ULL27 is decreased as compared to the ULL27 in the subject prior to the administration
of LYT-100. In some embodiments, the disclosure provides a method for decreasing the
ULL27 in a subject comprising administering to the subject LYT-100, wherein the ULL27
is decreased by at least 2% as compared to the ULL27 in the subject prior to the administration
of LYT-100. In some embodiments, the disclosure provides a method for decreasing the
ULL27 in the limb of a subject comprising administering to the subject LYT-100, wherein
the ULL27 is decreased by at least 3%, at least 4%, at least 5%, at least 6%, at least
7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%,
at least 14% at least 15%, at least 16%, at least 17%, at least 18%, at least 19%,
or at least 20% as compared to the ULL27 in the subject prior to the administration
of LYT-100. In some embodiments, the disclosure provides a method for decreasing the
ULL27 in the limb of a subject comprising administering to the subject LYT-100, wherein
the ULL27 is decreased by greater than 20% as compared to the ULL27 in the subject
prior to the administration of LYT-100.
[0200] Lymphedema Life Impact Scale (LLIS) is a comprehensive lymphedema-specific instrument
to measure impairments, activity limitations, and participation restrictions in patients
with any extremity lymphedema. It is an 18-question assessment tool that includes
physical, psychosocial, and functional domains. The Life Impact Scale is designed
to work in conjunction with an impairment calculator to determine the impairment severity.
In some embodiments, the disclosure provides methods for reducing or lowering the
LLIS of a subject (e.g., lessening the impairment severity) comprising administering
to the subject a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments,
the deuterium-enriched pirfenidone is LYT-100. Thus, in some embodiments, the disclosure
provides methods for reducing the LLIS in a subject with edema, e.g., lymphedema,
comprising administering an effective amount of LYT-100. In some embodiments, provided
herein are methods for treating lymphedema comprising administering to a subject having
lymphedema in at least one limb a deuterium-enriched pirfenidone compound, e.g., LYT-100,
wherein the LLIS in the subject is decreased as compared to the LLIS in the subject
prior to the administration of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100. In some embodiments, LLIS is decreased by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more as compared to the LLIS in the
subject prior to the administration of the deuterium-enriched pirfenidone compound.
In some embodiments, the disclosure provides a method for decreasing the LLIS in a
subject comprising administering to the subject LYT-100, wherein the LLIS is decreased.
In some embodiments, the disclosure provides a method for decreasing the LLIS in a
subject comprising administering to the subject LYT-100, wherein the LLIS is decreased
as compared to the LLIS in the subject prior to the administration of LYT-100. In
some embodiments, the disclosure provides a method for decreasing the LLIS in a subject
comprising administering to the subject LYT-100, wherein the LLIS is decreased by
at least 2% as compared to the LLIS in the subject prior to the administration of
LYT-100. In some embodiments, the disclosure provides a method for decreasing the
LLIS in a subject comprising administering to the subject LYT-100, wherein the LLIS
is decreased by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at
least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at
least 14% at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or
at least 20% as compared to the LLIS in the subject prior to the administration of
LYT-100. In some embodiments, the disclosure provides a method for decreasing the
LLIS in a subject comprising administering to the subject LYT-100, wherein the LLIS
is decreased by greater than 20% as compared to the LLIS in the subject prior to the
administration of LYT-100.
[0201] Functional Assessment of Cancer Therapy breast cancer-specific quality of life tool
(FACT-B +4) is a five-point Likert scale where a greater quality of life corresponds
to a high score once negatively phrased item scores are reversed. Scores are calculated
by summing the subscale scores for physical well-being, social well-being, emotional
well-being, functional well-being, and breast cancer additional concerns subscales.
In some embodiments, the disclosure provides methods for increasing the FACT-B+4 score
of a subject (e.g., improving quality of life) comprising administering to the subject
a deuterium-enriched pirfenidone compound disclosed herein, for example, a compound
of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched
pirfenidone is LYT-100. Thus, in some embodiments, the disclosure provides methods
for increasing the FACT-B+4 score in a subject with edema, e.g., lymphedema, comprising
administering an effective amount of LYT-100. In some embodiments, provided herein
are methods for treating lymphedema comprising administering to a subject having lymphedema
a deuterium-enriched pirfenidone compound, e.g., LYT-100, wherein the FACT-B+4 score
is increased in the subject as compared to the FACT-B+4 score in the subject prior
to the administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100.
In some embodiments, the FACT-B +4 score is increased by 2%, 3%, 4%, 5%, 6%, 7%, 8%,
9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more as compared to the FACT-B+4
score in a subject prior to the administration of the deuterium-enriched pirfenidone
compound. In some embodiments, the disclosure provides a method for increasing the
FACT-B+4 in a subject comprising administering to the subject LYT-100, wherein the
FACT-B+4 is increased. In some embodiments, the disclosure provides a method for increasing
the FACT-B+4 in a subject comprising administering to the subject LYT-100, wherein
the FACT-B+4 is increased as compared to the FACT-B+4 in the subject prior to the
administration of LYT-100. In some embodiments, the disclosure provides a method for
increasing the FACT-B+4 in a subject comprising administering to the subject LYT-100,
wherein the FACT-B+4 is increased by at least 2% as compared to the FACT-B+4 in the
subject prior to the administration of LYT-100. In some embodiments, the disclosure
provides a method for increasing the FACT-B+4 in a subject comprising administering
to the subject LYT-100, wherein the FACT-B+4 is increased by at least 3%, at least
4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%,
at least 11%, at least 12%, at least 13%, at least 14% at least 15%, at least 16%,
at least 17%, at least 18%, at least 19%, or at least 20% as compared to the FACT-B+4
in the subject prior to the administration of LYT-100. In some embodiments, the disclosure
provides a method for increasing the FACT-B+4 in a subject comprising administering
to the subject LYT-100, wherein the FACT-B+4 is increased by greater than 20% as compared
to the FACT-B+4 in the subject prior to the administration of LYT-100.
[0202] Lymphedema Quality of Life measure for lymphedema of the limbs (LYMQOL) covers four
domains: symptoms, body image/appearance, function, and mood. It also includes an
overall quality of life rating. Subjects with more severe limb dysfunction have higher
scores correspodning to lower quality of life. In some embodiments, the disclosure
provides methods for decreasing the overall LYMQOL of a subject comprising administering
to the subject a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments,
the deuterium-enriched pirfenidone is LYT-100. Thus, in some embodiments, the disclosure
provides methods for decreasing the overall LYMQOL in a subject with edema, e.g.,
lymphedema, comprising administering an effective amount of LYT-100. In some embodiments,
provided herein are methods for treating lymphedema comprising administering to a
subject having lymphedema in at least one limb a deuterium-enriched pirfenidone compound,
e.g., LYT-100, wherein the LYMQOL is decreased in the subject as compared to the LYMQOL
in the subject prior to the administration of the deuterium-enriched pirfenidone compound,
e.g., LYT-100. In some embodiment, LYMQOL is decreased by 2%, 3%, 4%, 5%, 6%, 7%,
8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more as compared to the overall
LYMQOL in the subject prior to administration of the deuterium-enriched pirfenidone
compound. In some embodiments, provided herein are methods for treating lymphedema
comprising administering to a subject having lymphedema in at least one limb a deuterium-enriched
pirfenidone compound, e.g., LYT-100, wherein the LYMQOL is decreased in the subject
as compared to the LYMQOL in the subject prior to the administration of the deuterium-enriched
pirfenidone compound, e.g., LYT-100. =In some embodiments, the LYMQOL is decreased
by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or
more as compared to the LYMQOL in a subject prior to the administration of the deuterium-enriched
pirfenidone compound. In some embodiments, the disclosure provides a method for decreasing
the LYMQOL in a subject comprising administering to the subject LYT-100, wherein the
LYMQOL is increased. In some embodiments, the disclosure provides a method for decreasing
the LYMQOL in a subject comprising administering to the subject LYT-100, wherein the
LYMQOL is decreased in the subject as compared to the LYMQOL in the subject prior
to the administration of LYT-100. In some embodiments, the disclosure provides a method
for decreasing the LYMQOL in a subject comprising administering to the subject LYT-100,
wherein the LYMQOL is decreased by at least 2% as compared to the LYMQOL in the subject
prior to the administration of LYT-100. In some embodiments, the disclosure provides
a method for decreasing the LYMQOL in a subject comprising administering to the subject
LYT-100, wherein the LYMQOL is decreased by at least 3%, at least 4%, at least 5%,
at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at
least 12%, at least 13%, at least 14% at least 15%, at least 16%, at least 17%, at
least 18%, at least 19%, or at least 20% as compared to the LYMQOL in the subject
prior to the administration of LYT-100. In some embodiments, the disclosure provides
a method for decreasing the LYMQOL in a subject comprising administering to the subject
LYT-100, wherein the LYMQOL is decreased by greater than 20% as compared to the LYMQOL
in the subject prior to the administration of LYT-100.
[0203] Disabilities of the Arm, Shoulder, and Hand score (DASH) is a 30-item disability/symptom
scale, scored 0 (no disability) to 100. Each item has five response options. The scores
for all items are then used to calculate a scale score ranging from 0 (no disability)
to 100 (most severe disability). Items ask about the degree of difficulty in performing
different physical activities because of the arm, shoulder, or hand problem (21 items),
the severity of each of the symptoms of pain, activity-related pain, tingling, weakness
and stiffness (5 items), and the problems impact on social activities, work, sleep,
and self-image (4 items). The DASH can detect and differentiate small and large changes
of disability over time after surgery in patients with upper-extremity musculoskeletal
disorders. A 10-point difference in mean DASH score is considered a significant change
indicating therapeutic effect. DASH score can be scored as raw, converted to a 0-100
score, or converted to a logit scale. In some embodiments, the disclosure provides
methods for decreasing the DASH score of a subject (e.g., reducing the disability/symptoms)
comprising administering to the subject a deuterium-enriched pirfenidone compound
disclosed herein, for example, a compound of Formula I, e.g., a compound listed in
Table 1. In some embodiments, the deuterium-enriched pirfenidone is LYT-100. Thus,
in some embodiments, the disclosure provides methods for decreasing the DASH score
in a subject with edema, e.g., lymphedema, comprising administering an effective amount
of LYT-100. In some embodiments, provided herein are methods for treating lymphedema
comprising administering to a subject having lymphedema in at least one limb a deuterium-enriched
pirfenidone compound, e.g., LYT-100, wherein the subject's DASH score is decreased
as compared to the subject's DASH score prior to the administatration of the deuterium-enriched
pirfenidone compound, e.g., LYT-100. In some embodiments, the DASH score of a subject
is decreased by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50% or more over a three month, six month, nine month, or twelve month period
as compared to the DASH score of the subject prior to administration of the deuterium-enriched
pirfenidone compound. In some embodiments, the disclosure provides a method for decreasing
the DASH score in a subj ect comprising administering to the subject LYT-100, wherein
the DASH score is decreased. In some embodiments, the disclosure provides a method
for decreasing the DASH score in a subj ect comprising administering to the subject
LYT-100, wherein the DASH score in the subject is decreased as compared to the DASH
score in the subject prior to the administration of LYT-100. In some embodiments,
the disclosure provides a method for decreasing the DASH score in a subj ect comprising
administering to the subject LYT-100, wherein the DASH score in the subject is decreased
by at least 5 points as compared to the DASH score in the subject prior to the administration
of LYT-100. In some embodiments, the disclosure provides a method for decreasing the
DASH score in a subject comprising administering to the subject LYT-100, wherein the
DASH score in the subject is decreased by at least 10 points as compared to the DASH
score in the subject prior to the administration of LYT-100. In some embodiments,
the disclosure provides a method for decreasing the DASH score in a subject comprising
administering to the subject LYT-100, wherein the DASH score in the subject is decreased
by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or
more over a three month, six month, nine month, or twelve month period as compared
to the DASH score of the subject prior to administration of the deuterium-enriched
pirfenidone compound. as compared to the DASH score in the subject prior to the administration
of LYT-100. In some embodiments, the disclosure provides a method for decreasing the
DASH score in a subject comprising administering to the subject LYT-100, wherein the
DASH score in the subject is decreased by greater than 10% as compared to the DASH
score in the subject prior to the administration of LYT-100.
[0204] Lymphedema Quality of Life Inventory (LQOLI) is the only HRQOL instrument developed
and tested in patients with different types of lymphedema. The questionnaire consists
of three parts: physical, psychosocial, and practical. In some embodiments, the disclosure
provides methods for decreasing the LQOLI of a subject comprising administering to
the subject a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments,
the deuterium-enriched pirfenidone is LYT-100. Thus, in some embodiments, the disclosure
provides methods for decreasing the LQOLI in a subject with edema, e.g., lymphedema,
comprising administering an effective amount of LYT-100. In some embodiments, the
LQOLI is decreased as compared to the LQOLI of the subject prior to deuterium-enriched
pirfenidone administration. Thus, in some embodiments, the disclosure provides methods
for decreasing the overall LQOLI in a subject with edema, e.g., lymphedema, comprising
administering an effective amount of LYT-100. In some embodiments, provided herein
are methods for treating lymphedema comprising administering to a subject having lymphedema
a deuterium-enriched pirfenidone compound, e.g., LYT-100, wherein the LQOLI is decreased
in the subject as compared to the LQOLI in the subject prior to the administration
of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments,
the disclosure provides a method for decreasing the LQOLI in a subject comprising
administering to the subject LYT-100, wherein the LQOLI is decreased. In some embodiments,
the disclosure provides a method for decreasing the LQOLI in a subject comprising
administering to the subj ect LYT-100, wherein the LQOLI is decreased in the subj
ect as compared to the LQOLI in the subject prior to the administration of LYT-100.
In some embodiments, the disclosure provides a method for decreasing the LQOLI in
a subject comprising administering to the subject LYT-100, wherein the LQOLI is decreased
by at least 2% as compared to the LQOLI in the subject prior to the administration
of LYT-100. In some embodiments, the disclosure provides a method for decreasing the
LQOLI in a subject comprising administering to the subject LYT-100, wherein the LQOLI
is decreased by greater than 20% as compared to the LQOLI in the subject prior to
the administration of LYT-100.
[0205] Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF) is an
inflammatory cytokine, and can be employed as a measure of the systemic inflammatory
response of the patient. It can be assessed with Luminex-bead inflammasome analysis
of pre- and post-treatment plasma samples. In some embodiments, the disclosure provides
methods for decreasing the G-CSF in a subject comprising administering to the subject
a deuterium-enriched pirfenidone compound disclosed herein, for example, a compound
of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched
pirfenidone is LYT-100. Thus, in some embodiments, the disclosure provides methods
for decreasing G-CSF in a subject with edema, e.g., lymphedema, comprising administering
an effective amount of LYT-100. In some embodiments, provided herein are methods for
treating lymphedema comprising administering to a subject having lymphedema a deuterium-enriched
pirfenidone compound, e.g., LYT-100, wherein G-CSF in the subject is decreased as
compared to G-CSF in the subject prior to the administration of the deuterium-enriched
pirfenidone compound, e.g., LYT-100. In some embodiments, there is a significant decrease
in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF). In
some embodiments, there is a decrease of at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more as compared to the G-CSF in a
subject prior to the administration of the deuterium-enriched pirfenidone compound.
In some embodiments, the disclosure provides a method for decreasing G-CSF in a subject
comprising administering to the subject LYT-100, wherein the G-CSF is decreased. In
some embodiments, the disclosure provides a method for decreasing the G-CSF in a subject
comprising administering to the subject LYT-100, wherein the G-CSF is decreased as
compared to the G-CSF in the subject prior to the administration of LYT-100. In some
embodiments, the disclosure provides a method for decreasing the G-CSF in a subject
comprising administering to the subject LYT-100, wherein the G-CSF is decreased by
at least 2% as compared to the G-CSF in the subject prior to the administration of
LYT-100. In some embodiments, the disclosure provides a method for decreasing the
G-CSF in a subject comprising administering to the subject LYT-100, wherein the G-CSF
is decreased by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at
least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at
least 14% at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or
at least 20% as compared to the G-CSF in the subject prior to the administration of
LYT-100. In some embodiments, the disclosure provides a method for decreasing the
G-CSF in a subject comprising administering to the subject LYT-100, wherein the G-CSF
is decreased by greater than 20% as compared to the G-CSF in the subject prior to
the administration of LYT-100.
[0206] In some embodiments, there is a significant change from baseline in cutaneous histological
architecture (CHA) based on histological specimens of lymphedema skin pre- and post-treatment
with LYT-100. This score is based on a scoring system evaluating dermal thickness
(0-5), internal mucin content (0-5), deep dermal collagen content (0-5), and perivascular
infiltrate (0-5), with a total sum score of 0-20. In some embodiments, the disclosure
provides methods for decreasing the CHA score of a subject comprising administering
to the subject a deuterium-enriched pirfenidone compound disclosed herein, for example,
a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments,
the deuterium-enriched pirfenidone is LYT-100. Thus, in some embodiments, the disclosure
provides methods for decreasing the CHA score in a subject with edema, e.g., lymphedema,
comprising administering an effective amount of LYT-100. In some embodiments, provided
herein are methods for treating lymphedema comprising administering to a subject having
lymphedema a deuterium-enriched pirfenidone compound, e.g., LYT-100, wherein the CHA
score in the subject is decreased as compared to the CHA score in the subject prior
to the administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100.
In some embodiments, there is a decrease of at least 50% in the CHA. In some embodiments,
the CHA decreases at least 40%, at least 30%, at least 25%, at least 20%, at least
15%, at least 10%, at least 5%, at least 2% or at least 1% as compared to the CHA
in the subject prior to administration of the deuterium-enriched pirfenidone compound,
e.g., LYT-100. In some embodiments, this decrease is seen within 3, 4 or 6 months.
In some embodiments, the disclosure provides a method for decreasing the CHA score
in a subject comprising administering to the subject LYT-100, wherein the CHA score
is decreased. In some embodiments, the disclosure provides a method for decreasing
the CHA score in a subject comprising administering to the subject LYT-100, wherein
the CHA score is decreased as compared to the CHA score in the subject prior to the
administration of LYT-100. In some embodiments, the disclosure provides a method for
decreasing the CHA score in a subject comprising administering to the subject LYT-100,
wherein the CHA score is decreased by at least 2% as compared to the CHA score in
the subject prior to the administration of LYT-100. In some embodiments, the disclosure
provides a method for decreasing the CHA score in a subject comprising administering
to the subject LYT-100, wherein the CHA score is decreased by at least 3%, at least
4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%,
at least 11%, at least 12%, at least 13%, at least 14% at least 15%, at least 16%,
at least 17%, at least 18%, at least 19%, or at least 20% as compared to the CHA score
in the subject prior to the administration of LYT-100. In some embodiments, the disclosure
provides a method for decreasing the CHA score in a subject comprising administering
to the subject LYT-100, wherein the CHA score is decreased by greater than 20% as
compared to the CHA score in the subject prior to the administration of LYT-100.
[0207] In some embodiments, the disclosure provides methods for reducing the skin thickness
of a subject comprising administering to the subject a deuterium-enriched pirfenidone
compound disclosed herein, for example, a compound of Formula I, e.g., a compound
listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.
Thus, in some embodiments, the disclosure provides methods for reducing the skin thickness
in a subject with edema, e.g., lymphedema, comprising administering an effective amount
of LYT-100. In some embodiments, provided herein are methods for treating lymphedema
comprising administering to a subject having lymphedema a deuterium-enriched pirfenidone
compound, e.g., LYT-100, wherein the skin thickness in the subject is decreased as
compared to the skin thickness in the subject prior to the administration of the deuterium-enriched
pirfenidone compound, e.g., LYT-100. In some embodiments, measurement of skin thickness
by caliper is reduced by at least 50% as compared to the skin thickness in the subject
prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100.
In some embodiments, measurement of skin thickness by caliper is reduced by at least
40%. 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, or 5% as compared to the skin thickness
in the subject prior to administration of the deuterium-enriched pirfenidone compound,
e.g., LYT-100. in some embodiments, skin thickness is reduced by 25% as compared to
the skin thickness in the subject prior to administration of the deuterium-enriched
pirfenidone compound, e.g., LYT-100. In some embodiments, this reduction is seen within
3, 4 or 6 months. In some embodiments, the disclosure provides a method for decreasing
the skin thickness in a subject comprising administering to the subject LYT-100, wherein
the skin thickness is decreased. In some embodiments, the disclosure provides a method
for decreasing the skin thickness in a subject comprising administering to the subject
LYT-100, wherein the skin thickness is decreased as compared to the skin thickness
in the subject prior to the administration of LYT-100. In some embodiments, the disclosure
provides a method for decreasing the skin thickness in a subject comprising administering
to the subject LYT-100, wherein the skin thickness is decreased by at least 10% as
compared to the skin thickness in the subject prior to the administration of LYT-100.
In some embodiments, the disclosure provides a method for decreasing the skin thickness
in a subject comprising administering to the subject LYT-100, wherein the skin thickness
is decreased by at least 15%, at least 16%, at least 17%, at least 18%, at least 19%,
at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%,
at least 26% at least 27%, at least 28%, at least 29%, at least 30%, at least 35%,
or at least 40% as compared to the skin thickness in the subject prior to the administration
of LYT-100. In some embodiments, the disclosure provides a method for decreasing the
skin thickness in a subject comprising administering to the subject LYT-100, wherein
the skin thickness is decreased by at least 20% as compared to the skin thickness
in the subject prior to the administration of LYT-100.
[0208] In some embodiments, the present disclosure relates to the use of deuterium-enriched
pirfenidone to treat, prevent, and/or ameliorate one or more symptoms associated with
edema. In some embodiments, the deuterium-enriched pirfenidone is LYT-100 or a pharmaceutically
acceptable salt thereof. In some embodiments, the present disclosure provides a method
of treating, preventing nad/or ameliorating one or more symptoms of edema, comprising
administering to a subject in need thereof an effective amount of a deuterium-enriched
pirfenidone, e.g., a compound of Formula I, e.g., a compound in Table 1. In some embodiments,
the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically acceptable salt
thereof.
[0209] In some embodiments, the present disclosure relates to the use of deuterium-enriched
pirfenidone to treat, prevent, and/or ameliorate one or more symptoms of lymphedema.
In some embodiments, the deuterium-enriched pirfenidone is LYT-100 or a pharmaceutically
acceptable salt thereof. In some embodiments, the present disclosure provides a method
of treating, preventing and/or ameliorating one or more symptoms of lymphedema, comprising
administering to a subject in need thereof an effective amount of a deuterium-enriched
pirfenidone, e.g., a compound of Formula I, e.g., a compound in Table 1. In some embodiments,
the deuterium-enriched pirfenidone administered to the subject in need thereof is
LYT-100, or a pharmaceutically acceptable salt thereof.
[0210] In some embodiments, the present disclosure relates to the use of deuterium-enriched
pirfenidone to treat, prevent, and/or ameliorate one or more symptoms of secondary
lymphedema. In some embodiments, the deuterium-enriched pirfenidone is LYT-100 or
a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure
provides a method of treating, preventing, and/or ameliorating one or more symptoms
of secondary lymphedema, comprising administering to a subject in need thereof an
effective amount of a deuterium-enriched pirfenidone, e.g., a compound of Formula
I, e.g., a compound in Table 1. In some embodiments, the deuterium-enriched pirfenidone
administered to the subject in need thereof is LYT-100, or a pharmaceutically acceptable
salt thereof.
[0211] In some embodiments, the present disclosure relates to the use of deuterium-enriched
pirfenidone to treat, prevent, and/or ameliorate one or more symptoms of breast cancer-related
arm lymphedema. In some embodiments, the deuterium-enriched pirfenidone is LYT-100
or a pharmacologically acceptable salt thereof. In some embodiments, the present disclosure
provides a method of treating, preventing, and/or ameliorating one or more symptoms
of breast cancer-related arm lymphedema, comprising administering to a subject in
need thereof an effective amount of a deuterium-enriched pirfenidone, e.g., a compound
of Formula I, e.g., a compound in Table 1. In some embodiments, the deuterium-enriched
pirfenidone administered to the subject in need thereof is LYT-100, or a pharmaceutically
acceptable salt thereof.
[0212] In some embodiments, the present disclosure relates to the use of deuterium-enriched
pirfenidone to treat, prevent, and/or ameliorate one or more symptoms of lymphedema
other than breast cancer-related arm lymphedema. In some embodiments, the deuterium-enriched
pirfenidone is LYT-100 or a pharmaceutically-acceptablesalt thereof. In some embodiments,
the present disclosure provides a method of treating, preventing, and/or ameliorating
one or more symptoms of lymphedema other than breast cancer-related arm lymphedema,
comprising administering to a subject in need thereof an effective amount of a deuterium-enriched
pirfenidone, e.g., a compound of Formula I, e.g., a compound in Table 1. In some embodiments,
the deuterium-enriched pirfenidone administered to the subject in need thereof is
LYT-100, or a pharmaceutically acceptable salt thereof.
[0213] In some embodiments, the present disclosure relates to the use of deuterium-enriched
pirfenidone to treat, prevent, and/or ameliorate one or more symptoms of primary lymphedema.
In some embodiments, the deuterium-enriched pirfenidone is LYT-100 or a pharmaceutically-acceptable
salt thereof. In some embodiments, the present disclosure provides a method of treating,
preventing, and/or ameliorating one or more symptoms of primary lymphedema, comprising
administering to a subject in need thereof an effective amount of a deuterium-enriched
pirfenidone, e.g., a compound of Formula I, e.g., a compound in Table 1. In some embodiments,
the deuterium-enriched pirfenidone administered to the subject in need thereof is
LYT-100, or a pharmaceutically acceptable salt thereof.
[0214] In some embodiments, the present disclosure relates to the use of deuterium-enriched
pirfenidone to treat, prevent, and/or ameliorate one or more symptoms of lymphatic
filariasis. In some embodiments, the deuterium-enriched pirfenidone is LYT-100 or
a pharmaceutically-acceptable salt thereof. In some embodiments, the present disclosure
provides a method of treating, preventing, and/or ameliorating one or more symptoms
of lymphatic filariasis, comprising administering to a subject in need thereof an
effective amount of a deuterium-enriched pirfenidone, e.g., a compound of Formula
I, e.g., a compound in Table 1. In some embodiments, the deuterium-enriched pirfenidone
administered to the subject in need thereof is LYT-100, or a pharmaceutically acceptable
salt thereof.
[0215] In some embodiments, the present disclosure relates to the use of deuterium-enriched
pirfenidone to treat, prevent, and/or ameliorate one or more symptoms of other lymphatic
and/or fibrotic disorders. Inflammation and fibrosis affect lymphatic flow, thus the
pirfenidone agents described herein, e.g., deuterium-enriched pirfenidone can be used
to treat other lymphatic flow conditions. As discussed herein, patients have lymphedema
beyond breast cancer-related arm lymphedema and pirfenidone agents described herein,
e.g., deuterium-enriched pirfenidone can be used to treat the underlying mechanisms
of other forms of secondary or primary lymphedema. In some embodiments, the pirfenidone
agents described herein, e.g., deuterium-enriched pirfenidone have anti-inflammatory
and/or anti-fibrotic activity and can be used to treat fibrotic diseases, including
IPF and FSGS. In some embodiments, the deuterium-enriched pirfenidone is LYT-100 or
a pharmaceutically-acceptablesalt thereof. In some embodiments, the present disclosure
provides a method of treating, preventing, and/or ameliorating one or more symptoms
of other lymphatic and/or fibrotic disorders, comprising administering to a subject
in need thereof an effective amount of deuterium-enriched pirfenidone. In some embodiments,
the deuterium-enriched pirfenidone administered to the subject in need thereof is
LYT-100, or a pharmaceutically acceptable salt thereof.
[0216] Lymphatic vessels are present in most tissues of the body. These vessels consist
of an extensive network of thin-walled vessels that drain protein-rich lymph from
extracellular spaces. Major functions of the lymphatic system include maintenance
of tissue fluid homeostasis, fatty acid absorption, and mediation of immune responses
under normal circumstances. The lymphatic system also plays key roles in disease processes
such lymphedema, fibrosis and inflammation. In such lymphatic disorders, lymphatic
flow is altered and balance of interstitial fluid perturbed. Consequently, maintaining
or restoring interstitial fluid balance and/or maintaining restoring lymphatic flow
constitutes one approach to the treatment of these disorders. Without wishing to be
bound by theory, administration of an agent that modulates, e.g., increases lymphatic
flow, to a subject with a lymphatic disorder can alleviate, treat or prevent the disorder.
[0217] In some embodiments, methods are provided herein for modulating and/or maintaining
interstitial fluid balance and/or lymphatic flow in a subject in need thereof. In
some embodiments, the modulation of lymphatic flow in a subject in need thereof comprises
increasing lymphatic flow in said subject. In some embodiments, the method comprises
administering an effective amount of a compound, e.g., an effective amount of deuterium-enriched
pirfenidone having the structure shown in Formula I. In some embodiments, the compound
is LYT-100. In some embodiments, methods are provided herein to treat a lymphatic
disorder described herein comprising modulating and/or maintaining interstitial fluid
balance and/or lymphatic flow. In some embodiments, the methods comprise increasing
lymphatic flow in a subject in need thereof. In some embodiments, the methods comprise
administering an effective amount of a compound, e.g., an effective amount of deuterium-enriched
pirfenidone having the structure shown in Formula I. In some embodiments, the compound
is LYT-100.
[0218] Further methods are provided herein, comprising reducing inflammation and/or fibrosis
in a subject having insufficient lymphatic flow, the method comprising administering
to a subject in need thereof an effective amount of deuterium-enriched pirfenidone
having the structure shown in Formula I. In some embodiments, the compound is LYT-100.
In some embodiments, methods are provided herein to treat a lymphatic disorder described
herein comprising reducing inflammation and/or fibrosis in a subject having insufficient
lymphatic flow. In some embodiments, the methods comprise administering an effective
amount of a compound, e.g., an effective amount of deuterium-enriched pirfenidone
having the structure shown in Formula I. In some embodiments, the compound is LYT-100.
[0219] In some embodiments, the deuterium-enriched pirfenidone compound disclosed herein
has the ability to effect one or more of the following: a) reduce tissue swelling,
b) reduce lymphatic fluid stasis or "pooling," c) reduce tissue fibrosis, d) reduce
tissue inflammation, e) reduce infiltration of leukocytes, f) reduce infiltration
of macrophages, g) reduce infiltration of naive and differentiated T-cells, h) reduce
TGF-β1 expression and reduce expression and/or activation of downstream mediators
(e.g., pSmad3), i) reduce levels of angiotensins and/or ACE, j) reduce collagen deposition
and/or scar formation, k) improve or increase lymphatic function, 1) improve or increase
lymph fluid transport (e.g., lymphatic flow), m) improve or increase lymphangiogenesis,
and/or n) improve or increase lymph pulsation frequency.
[0220] Thus, disclosed herein are methods for treating a subject, including a human subject,
having or suspected of having edema, e.g., lyphedema or for preventing such disorder
in a subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein
(e.g., compound of Formula I, including, e.g., LYT-100), or a pharmaceutically acceptable
salt, solvate, or prodrug thereof; so as to effect one or more of a) - n) above during
the treatment of the disorder.
[0221] Thus, disclosed herein are methods for treating a subject, including a human subject,
having or suspected of having edema, e.g., lymphedema or for preventing edema, e.g.,
lymphedema in a subject prone to edema, e.g., lymphedema; comprising administering
to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone
compound as disclosed herein (e.g., compound of Formula I, including, e.g., LYT-100),
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to effect
one or more of a) - n) above during the treatment of edema, e.g., lymphedema.
[0222] In some embodiments, the disclosure provides methods for reducing tissue swelling
in a subject, including a human subject, having or suspected of having edema, e.g.,
lymphedema, or for preventing tissue swelling in a subject prone to edema or lymphedema;
comprising administering to the subject a therapeutically effective amount of a deuterium-enriched
pirfenidone compound as disclosed herein, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt,
solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone
is LYT-100.
[0223] In some embodiments, the disclosure provides methods for reducing lymphatic fluid
stasis or pooling in a subject, including a human subject, having or suspected of
having edema, e.g., lymphedema, or for preventing lymphatic fluid stasis or pooling
in a subject prone to edema or lymphedema; comprising administering to the subject
a therapeutically effective amount of a deuterium-enriched pirfenidone compound as
disclosed herein, for example, a compound of Formula I, e.g., a compound listed in
Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug
thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.
[0224] In some embodiments, the disclosure provides methods for improving or increasing
lymph fluid transport (e.g., increasing lymphatic flow) in a subject, including a
human subject, having or suspected of having edema, e.g., lymphedema, or for improving
or increasing lymph fluid transport (e.g., increasing lymphatic flow) in a subject
prone to edema or lymphedema; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
for example, a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments,
the deuterium-enriched pirfenidone is LYT-100.
[0225] In some embodiments, the disclosure provides methods for reducing tissue fibrosis
in a subject, including a human subject, having or suspected of having edema, e.g.,
lymphedema, or for preventing tissue fibrosis in a subject prone to edema or lymphedema;
comprising administering to the subject a therapeutically effective amount of a deuterium-enriched
pirfenidone compound as disclosed herein, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt,
solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone
is LYT-100.
[0226] In some embodiments, the disclosure provides methods for reducing tissue inflammation
in a subject, including a human subject, having or suspected of having edema, e.g.,
lymphedema, or for preventing tissue inflammation in a subject prone to edema or lymphedema;
comprising administering to the subject a therapeutically effective amount of a deuterium-enriched
pirfenidone compound as disclosed herein, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt,
solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone
is LYT-100.
[0227] In some embodiments, the disclosure provides methods for reducing infiltration of
leukocytes in a subject, including a human subject, having or suspected of having
edema, e.g., lymphedema, or for preventing infiltration of leukocytes in a subject
prone to edema or lymphedema; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
for example, a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments,
the deuterium-enriched pirfenidone is LYT-100.
[0228] In some embodiments, the disclosure provides methods for reducing infiltration of
macrophages in a subject, including a human subject, having or suspected of having
edema, e.g., lymphedema, or for preventing infiltration of macrophages in a subject
prone to edema or lymphedema; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
for example, a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments,
the deuterium-enriched pirfenidone is LYT-100.
[0229] In some embodiments, the disclosure provides methods for reducing infiltration of
naive and differentiated T-cells in a subject, including a human subject, having or
suspected of having edema, e.g., lymphedema, or for preventing infiltration of naive
and differentiated T-cells in a subject prone to edema or lymphedema; comprising administering
to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone
compound as disclosed herein, for example, a compound of Formula I, e.g., a compound
listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate,
or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.
[0230] In some embodiments, the disclosure provides methods for reducing TGF-β1 expression
and reducing expression and/or activation of downstream mediators (e.g., pSmad3) in
a subject, including a human subject, having or suspected of having edema, e.g., lymphedema,
or for preventing TGF-β1 expression and preventing expression and/or activation of
downstream mediators (e.g., pSmad3)in a subject prone to edema or lymphedema; comprising
administering to the subject a therapeutically effective amount of a deuterium-enriched
pirfenidone compound as disclosed herein, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt,
solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone
is LYT-100.
[0231] In some embodiments, the disclosure provides methods for reducing levels of angiotensins
and/or ACE in a subject, including a human subject, having or suspected of having
edema, e.g., lymphedema, or for preventing levels of angiotensins and/or ACE in a
subject prone to edema or lymphedema; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
for example, a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments,
the deuterium-enriched pirfenidone is LYT-100.
[0232] In some embodiments, the disclosure provides methods for improving or increasing
lymphatic function in a subject, including a human subject, having or suspected of
having edema, e.g., lymphedema, or for improving or increasing lymphatic function
in a subject prone to edema or lymphedema; comprising administering to the subject
a therapeutically effective amount of a deuterium-enriched pirfenidone compound as
disclosed herein, for example, a compound of Formula I, e.g., a compound listed in
Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug
thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.
[0233] In some embodiments, the disclosure provides methods for reducing collagen deposition
and/or scar formation in a subject, including a human subject, having or suspected
of having edema, e.g., lymphedema, or for preventing collagen deposition and/or scar
formation in a subject prone to edema or lymphedema; comprising administering to the
subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound
as disclosed herein, for example, a compound of Formula I, e.g., a compound listed
in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug
thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.
[0234] In some embodiments, the disclosure provides methods for improving or increasing
lymphangiogenesis in a subject, including a human subject, having or suspected of
having edema, e.g., lymphedema, or for improving or increasing lymphangiogenesis in
a subject prone to edema or lymphedema; comprising administering to the subject a
therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed
herein, for example, a compound of Formula I, e.g., a compound listed in Table 1,
e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the deuterium-enriched pirfenidone is LYT-100.
[0235] In some embodiments, the disclosure provides methods for improving or increasing
lymph pulsation frequency in a subject, including a human subject, having or suspected
of having edema, e.g., lymphedema, or for improving or increasing lymph pulsation
frequency in a subject prone to edema or lymphedema; comprising administering to the
subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound
as disclosed herein, for example, a compound of Formula I, e.g., a compound listed
in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug
thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.
[0236] Provided herein are methods for the treatment, prevention, and/or amelioration of
edema, e.g., lymphedema, wherein cellulitis is reduced, comprising administering to
a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100.
[0237] Provided herein are methods for the treatment, prevention, and/or amelioration of
cellulitis, comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including e.g., LYT-100.
[0238] In any of the above-described methods for treating, preventing, or ameliorating one
or more symptoms of edema or lymphedema, the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is administered orally twice a day, for a total daily dose of 100-1500
mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700,
750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In
some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is
750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily
dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is administered
orally 750 mg twice daily. In some embodiments, the deuterium-enriched pirfenidone
is administered orally 500 mg twice daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 250 mg twice daily.
[0239] In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100,
is administered orally once a day, for a total daily dose of 100-1500 mg. In some
embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900,
1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments,
the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some
embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250
mg. In some embodiments, the deuterium-enriched pirfenidone is administered orally
1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone is administered
orally 1000 mg once daily. In some embodiments, the deuterium-enriched pirfenidone
is administered orally 750 mg once daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 500 mg once daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 250 mg once daily.
[0240] In any of the above-described embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100 is administered orally three times a day, for a total daily dose of
100-1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500,
600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is
1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the
daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments,
the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone
is administered orally 500 mg three times daily. In some embodiments, the deuterium-enriched
pirfenidone is administered orally 333 mg three times daily. In some embodiments,
the deuterium-enriched pirfenidone is administered orally 166 mg three times daily.
[0241] In some embodiments, the deuterium-enriched pirfenidone is in tablet form. In some
embodiments, the deuterium-enriched pirfenidone is taken orally with food.
[0242] Thus, provided herein are methods for the treatment, prevention, and/or amelioration
of edema, e.g.lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including e.g., LYT-100, wherein the deuterium-enriched pirfenidone compound
is administered orally twice a day, for a total daily dose of 100-1500 mg. In some
embodiments, provided herein are methods for the treatment, prevention, and/or amelioration
of edeme, e.g., lymphedema comprising administering to a subject in need thereof LYT-100,
wherein LYT-100 is administered orally twice a day, for a total daily dose of 100-1500
mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100, is 1000 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 750 mg. In some
embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100 is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone
compound, e.g., LYT-100 is 250 mg. In some embodiments, the deuterium-enriched pirfenidone
compound, e.g., LYT-100 is administered orally 750 mg twice daily. In some embodiments,
the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally
500 mg twice daily. In some embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is administered orally 250 mg twice daily.
[0243] In some embodiments, provided herein are methods for the treatment, prevention, and/or
amelioration of edema, e.g., lymphedema comprising administering to a subject in need
thereof a deuterirum-enriched pirfenidone compound, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, wherein the deuterirum-enriched
pirfenidone compound is administered orally once a day, for a total daily dose of
100-1500 mg. In some embodiments, provided herein are methods for the treatment, prevention,
and/or amelioration of edema, e.g., lymphedema comprising administering to a subject
in need thereof LYT-100, wherein LYT-100, is administered orally once a day, for a
total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100 is 1500 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1000 mg. In some
embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100 is 500 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 250 mg. In some
embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered
orally 1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone
compound, e.g., LYT-100, is administered orally 1000 mg once daily. In some embodiments,
the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally
750 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound,
e.g., LYT-100, is administered orally 500 mg once daily. In some embodiments, the
deuterium-enriched pirfenidone compound, e.g., LYT-100 is administered orally 250
mg once daily.
[0244] Thus, provided herein are methods for the treatment, prevention, and/or amelioration
of edema, e.g., lymphedema comprising administering to a subject in need thereof a
deuterium-enriched pirfenidone compound, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, wherein the deuterium-enriched
pirfenidone compound is administered orally three times daily, for a total daily dose
of 100-1500 mg. In some embodiments, provided herein are methods for the treatment,
prevention, and/or amelioration of edema, e.g., lymphedema comprising administering
to a subject in need thereof LYT-100, wherein LYT-100 is administered orally three
times a day, for a total daily dose of 100-1500 mg. In some embodiments, the daily
dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In
some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g.,
LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched
pirfenidone compound, e.g., LYT-100, is 750 mg. In some embodiments, the daily dose
of the deuterium-enriched pirfenidone compound, e.g., LYT-100 is 500 mg. In some embodiments,
the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100 is 250
mg. In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100
is administered orally 500 mg three times daily. In some embodiments, the deuterium-enriched
pirfenidone compound, e.g., LYT-100, is administered orally 333 mg three timese daily.
In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is
administered orally 166 mg twice daily.
[0245] In other embodiments, the deuterium-enriched pirfenidone compound is administered
orally at a total daily dose of 100-2500 mg. In some embodiments, the deuterium-enriched
pirfenidone compound is administered orally at a total daily dose of 100-2000 mg.
In some embodiments, the deuterium-enriched pirfenidone compound is administered orally
at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-enriched
pirfenidone compound is administered orally at a total daily dose of 100-1000 mg.
In some embodiments, the deuterium-enriched pirfenidone compound is administered orally
at a total daily dose of 100-500 mg. In some embodiments, the daily dose is selected
from 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300,
1400, 1500, 1600, 1700,1800, 1900, 2000, 2100, 2200, 2300, 2400, and 2500 mg/day.
In some embodiments, the deuterium-enriched pirfenidone compound is administered orally
three times/day (TID). In some embodiments, the deuterium-enriched pirfenidone compound
is administered orally two times/day (BID). In some embodiments, the deuterium-enriched
pirfenidone compound is administered orally once daily (QD). In any of these embodiments,
the deuterium-enriched pirfenidone compound has the structure of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100.
[0246] In some embodiments, methods described herein include escalation of doses of deuterium-enriched
pirfenidone over a certain period until the full maintenance dose is reached. In some
embodiments, the escalation period is 7 days. In some embodiments, the escalation
period is 14 days. In some embodiments, the escalation period is 21 days. In some
embodiments, the methods described herein include reducing a dose. In any of these
embodiments, the daily dose is administered in one dose, or split into two or three
doses, i.e., administration is once, twice or three times daily.
[0247] In some embodiments, the daily dose is escalated from 250 mg to 500 mg. In some embodiments,
the daily dose is escalated from 250 mg to 750 mg, wherein a 500 mg step is optionally
included. In some embodiments, the daily dose is escalated from 250 mg to 1000 mg,
wherein a 500 mg step and/or a 750 mg step is optionally included. In some embodiments,
the daily dose is escalated from 250 mg to 1500 mg, wherein a 500 mg step and/or a
750 mg step and/or a 100 mg step is optionally included. In some embodiments, the
daily dose is escalated from 500 mg to 750 mg. In some embodiments, the daily dose
is escalated from 500 mg to 1000 mg, wherein a 750 mg step is optionally included.
In some embodiments, the daily dose is escalated from 500 mg to 1500 mg, wherein a
750 mg step and/or 100 mg step is optionally included. In any of these embodiments,
the daily dose is administered in one dose, or split into two or three doses, i.e.,
administration is once, twice or three times daily.
[0248] In some embodiments, the daily dose is escalated from 250 mg to 500 mg over a period
of 5 days. In some embodiments, the daily dose is escalated from 250 mg to 750 mg
over a period of 5 days, wherein a 500 mg step is optionally included. In some embodiments,
the daily dose is escalated from 250 mg to 1000 mg over a period of 5 days, wherein
a 500 mg step and/or a 750 mg step is optionally included. In some embodiments, the
daily dose is escalated from 250 mg to 1500 mg over a period of 5 days, wherein a
500 mg step and/or a 750 mg step and/or a 100 mg step is optionally included. In some
embodiments, the daily dose is escalated from 500 mg to 750 mg over a period of 5
days. In some embodiments, the daily dose is escalated from 500 mg to 1000 mg over
a period of 5 days, wherein a 750 mg step is optionally included. In some embodiments,
the daily dose is escalated from 500 mg to 1500 mg over a period of 5 days, wherein
a 750 mg step and/or 100 mg step is optionally included. In any of these embodiments,
the daily dose is administered in one dose, or split into two or three doses, i.e.,
administration is once, twice or three times daily.
[0249] In some embodiments, the daily dose is escalated from 500 mg to 250 mg over a period
of 5 days. In some embodiments, the daily dose is reduced from 750 mg to 250 mg over
a period of 5 days, wherein a 500 mg step. In some embodiments, the daily dose is
reduced from 1000 mg to 250 mg over a period of 5 days, wherein a 750 mg step and/or
a 500 mg step is optionally included. In some embodiments, the daily dose is reduced
from 1500 mg to 250 over a period of 5 days wherein a 1000 mg step and/or a 750 mg
step and/or a 500 mg step is optionally included. In some embodiments, the daily dose
is reduced from 750 mg to 500 mg over a period of 5 days. In some embodiments, the
daily dose is reduced from 1000 mg to 500 mg over a period of 5 days, wherein 750
mg step is optionally included. In some embodiments, the daily dose is reduced from
1500 mg to 500 mg over a period of 5 days, wherein a 100 mg step and/or a 750 mg step
is optionally included. In any of these embodiments, the daily dose is administered
in one dose, or split into two or three doses, i.e., administration is once, twice
or three times daily.
[0250] In some embodiments, the daily dose is escalated from 250 mg to 500 mg over a period
of 14 days. In some embodiments, the daily dose is escalated from 250 mg to 750 mg
over a period of 14 days, wherein a 500 mg step is optionally included. In some embodiments,
the daily dose is escalated from 250 mg to 1000 mg over a period of 14 days, wherein
a 500 mg step and/or a 750 mg step is optionally included. In some embodiments, the
daily dose is escalated from 250 mg to 1500 mg over a period of 14 days, wherein a
500 mg step and/or a 750 mg step and/or a 100 mg step is optionally included. In some
embodiments, the daily dose is escalated from 500 mg to 750 mg over a period of 14
days. In some embodiments, the daily dose is escalated from 500 mg to 1000 mg over
a period of 14 days, wherein a 750 mg step is optionally included. In some embodiments,
the daily dose is escalated from 500 mg to 1500 mg over a period of 14 days, wherein
a 750 mg step and/or 100 mg step is optionally included. In any of these embodiments,
the daily dose is administered in one dose, or split into two or three doses, i.e.,
administration is once, twice or three times daily.
[0251] In some embodiments, the daily dose is escalated from 250 mg to 500 mg from day 1
to day7 and then escalated from 500 mg to 1000mg from day 7 to day 14. In some embodiments,
the escalation from 500 mg to 1000 mg includes a 750 mg step. In some embodiments,
the daily dose is escalated from 500 mg to 750 mg from day 1 to day7 and then escalated
from 750 mg to 1000mg from day 7 to day 14. In any of these embodiments, the daily
dose is administered in one dose, or split into two or three doses, i.e., administration
is once, twice or three times daily.
[0252] In some embodiments, the daily dose is escalated from 250 mg to 500 mg over a period
of 21 days. In some embodiments, the daily dose is escalated from 250 mg to 750 mg
over a period of 21 days, wherein a 500 mg step is optionally included. In some embodiments,
the daily dose is escalated from 250 mg to 1000 mg over a period of 21 days, wherein
a 500 mg step and/or a 750 mg step is optionally included. In some embodiments, the
daily dose is escalated from 250 mg to 1500 mg over a period of 21 days, wherein a
500 mg step and/or a 750 mg step and/or a 100 mg step is optionally included. In some
embodiments, the daily dose is escalated from 500 mg to 750 mg over a period of 21
days. In some embodiments, the daily dose is escalated from 500 mg to 1000 mg over
a period of 21 days, wherein a 750 mg step is optionally included. In some embodiments,
the daily dose is escalated from 500 mg to 1500 mg over a period of 21 days, wherein
a 750 mg step and/or 100 mg step is optionally included. In any of these embodiments,
the daily dose is administered in one dose, or split into two or three doses, i.e.,
administration is once, twice or three times daily.
[0253] In some embodiments, the daily dose is escalated from 250 mg to 500 mg from day 1
to day 7, then escalated from 500 mg to 750 mg from day 7 to day 14, and then escalated
from 750 mg to 1000 mg from day 14 to day 21. In some embodiments, the daily dose
is escalated from 500 mg to 750 mg from day 1 to day7, then escalated from 750 mg
to 1000mg from day 7 to day 14, then escalated from 1000 mg to 1500 mg. In any of
these embodiments, the daily dose is administered in one dose, or split into two or
three doses, i.e., administration is once, twice or three times daily.
[0254] In a prophylactic context, the pharmaceutical composition of the invention can be
administered at any time before or after an event, for example, radiation therapy,
chemotherapy, or surgical lymph node dissection, which places a subject at risk of
or susceptible to lymphatic injury and/or developing edema. In some embodiments, the
pharmaceutical composition is administered prophylactically up to about one week before
the event, such as 1, 2, 3, 4, 5, 6, or 7 days before the event. In some instances,
the pharmaceutical composition is administered prophylactically on the same day as
the event. In some embodiments, the pharmaceutical composition is administered prophylactically
within six weeks of the event, for example, within about 1, 2, 3, 4, 5, or 6 days,
or within about 1, 2, 3, 4, 5 or 6 weeks of the event. In some embodiments, the pharmaceutical
composition is administered prophylactically for about 2-4 weeks or for about 1, 2,
3, 4, 5, or 6 weeks.
[0255] In one embodiment, methods of treating lymphedema in a subject comprising administering
LYT-100 are provided herein, wherein the treatment duration is selected from 1 week,
2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,
11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19
weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, and 25 weeks, and any increment
therein.
[0256] In one embodiment, methods of treating lymphedema in a subject comprising administering
LYT-100 are provided herein, wherein the treatment duration is selected from 1 month,
2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10
months, 11 months, or 12 months, and any increment therein. In one embodiment, methods
of treating lymphedema in a subject comprising administering LYT-100 are provided
herein, wherein the treatment duration is one year, 2 years, 3 years, 4 years, 5 years
or greater.
[0257] In some embodiments, LYT-100 may be administered with or without food. In some embodiments,
LYT-100 is administered with food. In some embodiments, LYT-100 is administered without
food.
[0258] In some embodiments, the pharmaceutical composition is administered topically once
a day or at least once a day. In another embodiment, the pharmaceutical composition
is administered topically twice a day or at least twice a day. Where the pharmaceutical
composition or method involves prevention of edema, particularly prevention of lymphedema,
the composition can be administered within about six weeks of a lymphatic injury,
for example within about two weeks of a lymphatic injury.
[0259] In some embodiments, the pharmaceutical composition is administered orally once a
day or at least once a day. In another embodiment, the pharmaceutical composition
is administered orally twice a day or at least twice a day. Where the pharmaceutical
composition or method involves prevention of edema, particularly prevention of lymphedema,
the composition can be administered within about six weeks of a lymphatic injury,
for example within about two weeks of a lymphatic injury.
Methods, Compositions and Dosing for Treating Interstitial Lung Disease
[0260] Idiopathic Pulmonary Fibrosis (IPF) afflicts approximately 100,000 people in the
United States, with the drugs nintedanib and pirfenidone as the only available treatments.
In preclinical studies, LYT-100 demonstrated favorable anti-fibrotic and anti-inflammatory
activity compared to pirfenidone.
[0261] Accordingly, provided herein is a method of treating an interstitial lung disease
(ILD), comprising administering to a subject in need thereof an effective amount of
deuterium-enriched pirfenidone having the structure:

or a pharmaceutically acceptable salt thereof, wherein ILD is treated in the subject.
[0262] In certain embodiments, the ILD is idiopathic pulmonary fibrosis (IPF). In some embodiments,
the ILD is chILD.
Clinical Advantages of Deuterium-Enriched Pirfenidone
[0263] Pirfenidone is a small molecule that has anti-fibrotic and anti-inflammatory effects.
Recent studies have suggested that this activity is due, at least in part, to inhibition
of production and activity of TGF-β.
Iyer et al., J. Pharmacol. Exp. Ther. 291: 367-373 (1999);
Tada et al., Clin. Exper. Pharmacol. Physiol. 28:522-527 (2001);
Oku et al., Eur. J. Pharmacol. 590:400-408 (2008). It is currently approved in the United States and elsewhere for oral administration
in the treatment of idiopathic pulmonary fibrosis (IPF).
Taniguchi et al., Eur. Respir. J. 35:821-829 (2010);
Noble et al., Lancet 377: 1760-1769 (2011);
King et al., N. Engl. J. Med. 370:2083-2092 (2014). Idiopathic pulmonary fibrosis (IPF) is a debilitating, progressive and fatal fibrotic
lung disease, with an approximate median survival of 2-5 years from the time of diagnosis.
IPF is one of the most commonly encountered interstitial lung diseases (II,Ds), with
increasing incidence and prevalence worldwide. Pirfenidone is one of two approved
therapies for the treatment of idiopathic pulmonary fibrosis (IPF). Randomised controlled
clinical trials and subsequent post hoc analyses have demonstrated that pirfenidone
reduces lung function decline, decreases mortality and improves progression-free survival.
[0264] However, Pirfenidone has a very short half-life in humans and consequently relatively
frequent dosing is required. The recommended daily maintenance dose of pirfenidone
is 801 mg three times per day (2403 mg·day-1) (a total of nine (9) pills per day at
full dose) with a 14-day titration period upon treatment initiation.
[0265] In addition, for patients with IPF to obtain the maximum benefits of pirfenidone
treatment, the adverse events (AEs) associated with pirfenidone need to be managed.
The most common AEs are gastrointestinal (GI) and skin-related adverse events, for
example, nausea, rash, diarrhea, fatigue, dyspepsia, anorexia, dizziness, gastroesophegeal
reflux disease, decreased appetite, decreased weight, photosensitivity, and cough.
In addition, several treatment-emergent adverse events have been reported, including
upper respiratory infection and bronchitis. A recent study in patients treated with
pirfenidone under a compassionate use program demonstrated that 44% of the patients
had an adverse event with pirfenidone, with only half of them continuing on pirfenidone
after a dose-reduction.
Raghu & Thickett. Thorax; 68: 605-608 (2013). Adverse events common with pirfenidone at 2403 mg/day include nausea, rash, fatigue,
diarrhea, vomiting, dyspepsia, photosensitivity, and anorexia.
Noble et al. Lancet; 377: 1760-69 (2011).
[0266] The results of several expanded cinical trials are summarized in
Lancaster et al., Eur Resp Rev 2017:26:170057 which reports treatment-emergent adverse events (TEAEs) as rates per 100 PEY (equivalent
to the frequency at which a physician might expect these TEAEs to occur if 100 patients
with IPF were followed for 1 year). Herein, it is noted that the most common reported
AEs leading to discontinuation are nausea, fatigue, diarrhea, and/or rash with frequencies
as high as 62.1 per 100 PEY (nausea), 27.6 per 100PEY (diarrhoea), 52.4 per 100PEY(
fatigue). In a single-centre, retrospective, observational study of 351 patients who
were receiving pirfenidone, 75% of reported AEs were GI-related, with loss of appetite
(17%) and nausea/vomiting (15%) being most frequent, similar to what was observed
in the phase III trials. The highest number of treatment discontinuations occurred
with appetite loss and nausea/vomiting. The incidience of AEs and discontinuation
increases with age. The proportion of patients with ADRs leading to dose modification/interruption
or discontinuation increased with increasing age: an ADR leading to dose modification/interruption
occurred in 32.7% of patients aged ≥80 years and in 18.0% of patients aged <65 years,
while an ADR leading to discontinuation occurred in 20.9% of patients aged ≥80 years
and in 7.5% of patients aged <65 years.
[0267] Several methods for managing AEs associated with pirfenidone have been proposed,
including varying the dose titration schedule by using a slower titration, employing
dose modifications, including reductions or interruptions (in phase III trials, dose
reductions and interruptions occurred in 46% and 41% of patients receiving pirfenidone,
respectively, with a median duration of 28 days and 14 days, respectively). Overall,
30% of pirfenidone patients had dose modifications and 29% discontinued permanently
due to AEs in phase III trials. In addition, modification of eating habits of the
patient is required when adjusting the pirfenidone dose. Taking pirfenidone with a
substantial amount of food, specifically the full dose at the end of a substantial
meal or spreading out the three capsules during the meal, may reduce the rate of pirfenidone
absorption and mitigate the onset of GI-related AEs.
[0268] Although slower titration and dose modification may assist in addressing patient
AEs, employing such measures has significant therapeutic impact, notably patients
who received pirfenidone 1197 mg/day were reported to experience greater lung function
decline than patients who were receiving the full dose of 2403 mg/day.
[0269] In addition, pirfenidone treatment has liver function Aesad therefore, monitoring
liver function is also important during pirfenidone treatment. Elevations of aspartate
transaminase (AST) and alanine transaminase (ALT) levels to >3× the upper limit of
normal (ULN) occurred in the phase III trials (3.2%), which were managed by dose modifications
or discontinuation. If AST and ALT elevations (>3× to ≤5× ULN) occur without symptoms
or hyperbilirubinaemia, the dose may be reduced or interrupted until values return
to normal. However, in cases in which the AST and ALT elevations (>3× to≤5× ULN) are
accompanied by hyperbilirubinaemia or if patients exhibit >5× ULN, pirfenidone must
be permanently discontinued.
[0270] In addition, patients must be monitored for drug-drug interactions, because the patients
taking other oral medications at the same time, may significantly affect pirfenidone
metabolism by inhibiting or inducing hepatic enzyme systems (cytochrome P450 1A2 (CYP1A2),
CYP3A4, P-glycoprotein). For example, for strong CYP1A2 inhibitors such as fluvoxamine
and enoxacin, pirfenidone should be reduced to 267 mg three times daily (801 mg·day-1).
For moderate CYP1A2 inhibitors, such as ciprofloxacin at a dosage of 750 mg twice
daily, pirfenidone should be reduced to 534 mg three times daily (1602 mg·day-1).
Patients should also be assessed for GI intolerance, skin reactions and liver enzyme
elevations.
[0271] Therefore, pirfenidone treatment requires various AE management strategies, including
a slower dose titration for initiating treatment, taking pirfenidone with substantial
meals, spacing capsules throughout the meal, diet modification, weight-based dosing
regimens and dose reductions and interruptions, as well as continual liver function
monitoring.
[0272] Accordingly, limitations of pirfenidone include: a short half-life of only about
2.5 hours; a high pill burden (of 9 capsules per day (TID dosing); poor tolerability
including nausea, diarrhea and photosensitivity; a high dose required for efficacy
that induces side effects; and significant interpatient variability.
[0273] In contrast, deuterium-enriched pirfenidone compounds address the deficiencies associated
with pirfenidone. The metabolism of pirfenidone is only partially understood. For
example, without wishing to be bound by theory, the methyl group is thought to be
susceptible to oxidation, which would lead to a corresponding hydroxymethyl metabolite,
"M1." M1 is thought to be further oxidized to a carboxylic acid metabolite, "M2" (
Wang et al., Biomedical Chromatography 2006, 20, 1375-1379). A third detected metabolite is believed to be a phase II product possibly originating
from M1 or M2.
[0274] Pirfenidone is a substituted pyridinone-based fibrosis modulator and/or collagen
infiltration modulator. The carbon-hydrogen bonds of pirfenidone contain a naturally
occurring distribution of hydrogen isotopes, namely 1H or protium (about 99.9844%),
2H or deuterium (about 0.0156%), and 3H or tritium (in the range between about 0.5
and 67 tritium atoms per 1018 protium atoms). Increased levels of deuterium incorporation
may produce a detectable Kinetic Isotope Effect (KIE) that could affect the pharmacokinetic,
pharmacologic and/or toxicologic profiles of such fibrosis modulators and/or collagen-infiltration
modulators in comparison with the compound having naturally occurring levels of deuterium.
[0275] Pirfenidone is likely metabolized in humans by oxidation of the methyl group. Other
sites on the molecule may also undergo transformations leading to metabolites with
as-yet-unknown pharmacology/toxicology. Limiting the production of these metabolites
has the potential to decrease the danger of the administration of such drugs and may
even allow increased dosage and concomitant increased efficacy. All of these transformations
can occur through polymorphically-expressed enzymes, thus exacerbating the interpatient
variability.
[0276] Accordingly, various deuteration patterns can be used to a) reduce or eliminate unwanted
metabolites, b) increase the half-life of the parent drug, c) decrease the number
of doses needed to achieve a desired effect, d) decrease the amount of a dose needed
to achieve a desired effect, e) increase the formation of active metabolites, if any
are formed, and/or f) decrease the production of deleterious metabolites in specific
tissues and/or create a more effective drug and/or a safer drug for polypharmacy,
whether the polypharmacy be intentional or not. The deuteration approach has strong
potential to slow the metabolism via various oxidative and racemization mechanisms.
[0277] In one embodiment, the deuterated compounds disclosed herein, e.g., LYT-100 maintain
the beneficial aspects of the corresponding non-isotopically enriched molecules while
substantially increasing the maximum tolerated dose, decreasing toxicity, increasing
the half-life (T1/2), lowering the maximum plasma concentration (Cmax) of the minimum
efficacious dose (MED), lowering the efficacious dose and thus decreasing the non-mechanism-related
toxicity, and/or lowering the probability of drug-drug interactions.
[0278] . In some embodiments, the deuterium-enriched pirfenidone compound used in the disclosed
methods has at least one of the following properties: a) decreased inter-individual
variation in plasma levels of the compound or a metabolite thereof as compared to
the non-isotopically enriched compound; b) increased average plasma levels of the
compound per dosage unit thereof as compared to the non-isotopically enriched compound;
c) decreased average plasma levels of at least one metabolite of the compound per
dosage unit thereof as compared to the non-isotopically enriched compound; d) increased
average plasma levels of at least one metabolite of the compound per dosage unit thereof
as compared to the non-isotopically enriched compound; and e) an improved clinical
effect during the treatment in the subject per dosage unit thereof as compared to
the non-isotopically enriched compound. Thus, disclosed herein are methods for treating
a subject, including a human, having or suspected of having edema, e.g., lymphedema,
or for preventing such disorder in a subject prone to the disorder; comprising administering
to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone
compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug
thereof; so as to effect one or more of a) - e) above during the treatment of the
disorder as compared to the corresponding non-isotopically enriched compound. In some
embodiments, the deuterium-enriched pirfenidone compound has at least two of the properties
a) through e) above. In some embodiments, the deuterium-enriched pirfenidone compound
has three or more of the properties a) through e) above.
[0279] In one embodiment is a method for the treatment, prevention, or amelioration of one
or more symptoms of edema, e.g., lymphedema.
[0280] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having edema, e.g., lymphedema, or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to effect
decreased inter-individual variation in plasma levels of the compound or a metabolite
thereof, during the treatment of the disorder as compared to the corresponding non-isotopically
enriched compound. In certain embodiments, the inter-individual variation in plasma
levels of the compounds as disclosed herein, or metabolites thereof, is decreased
by greater than about 2%, greater than about 5%, greater than about 10%, greater than
about 15%, greater than about 20%, greater than about 25%, greater than about 30%,
greater than about 40%, or by greater than about 50% (including any numerical increment
between the listed percentages) as compared to the corresponding non-isotopically
enriched compound.
[0281] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having edema, e.g., lymphedema, or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to affect
increased average plasma levels of the compound or decreased average plasma levels
of at least one metabolite of the compound per dosage unit as compared to the corresponding
non-isotopically enriched compound. In certain embodiments, the average plasma levels
of the compound as disclosed herein are increased by greater than about 2%, greater
than about 5%, greater than about 10%, greater than about 15%, greater than about
20%, greater than about 25%, greater than about 30%, greater than about 40%, or by
greater than about 50% (including any numerical increment between the listed percentages)
as compared to the corresponding non-isotopically enriched compounds. In certain embodiments,
the average plasma levels of a metabolite of the compound as disclosed herein are
decreased by greater than about 2%, greater than about 5%, greater than about 10%,
greater than about 15%, greater than about 20%, greater than about 25%, greater than
about 30%, greater than about 40%, or by greater than about 50% (including any numerical
increment between the listed percentages) as compared to the corresponding non-isotopically
enriched compounds.
[0283] In some embodiments, the compound has a decreased metabolism by at least one polymorphically-expressed
cytochrome P
450 isoform in the subject per dosage unit thereof as compared to the non-isotopically
enriched compound.
[0284] In some embodiments, the cytochrome P
450 isoform is selected from CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
[0285] In some embodiments, the compound is characterized by decreased inhibition of at
least one cytochrome P
450 or monoamine oxidase isoform in the subject per dosage unit thereof as compared to
the non-isotopically enriched compound.
[0286] In certain embodiments, the cytochrome P
450 or monoamine oxidase isoform is selected from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13,
CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1,
CYP2S1, CYP3A4, CYP3A5, CYP3ASP1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3,
CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1,
CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1,
CYP27B1, CYP39, CYP46, CYP51, MAO
A, and MAO
B.
[0287] In some embodiments, the deuterium-enriched pirfenidone compound has at least one
of the following properties: a) a half-life greater than 2.5 hours; b) a decreased
pill burden; c) increased patient tolerability; d) a lower efficacious dose; e) increased
bioavailability; f) increased Cmax; and g) increase in systemic exposure during the
treatment in the subject per dosage unit thereof as compared to the non-isotopically
enriched compound. Disclosed herein are methods for treating a subject, including
a human, having or suspected of having edema, e.g., lymphedema, or for preventing
such disorder in a subject prone to the disorder; comprising administering to the
subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound
as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof;
so as to effect one or more of a) - g) above during the treatment of the disorder
as compared to the corresponding non-isotopically enriched compound.
[0288] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having edema, e.g., lymphedema, or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to effect
a longer half-life. In some embodiments, the half-life of the deuterium-enriched pirfenidone
compounds as disclosed herein, or metabolites thereof, is increased by greater than
about 2%, greater than about 5%, greater than about 10%, greater than about 15%, greater
than about 20%, greater than about 25%, greater than about 30%, greater than about
40%, by greater than about 50%, by greater than about 60%, by greater than about 70%,
by greater than about 80%, by greater than about 90%, or by greater than about 100%
(including any numerical increment between the listed percentages) as compared to
the corresponding non-isotopically enriched compound. In some embodiments, the half-life
of the deuterium-enriched pirfenidone compounds as disclosed herein, or metabolites
thereof, is increased by about 1.5-fold, increased by about 2-fold, greater than about
2-fold, greater than about 3-fold, greater than about 4-fold, greater than about greater
than about 5-fold, greater than about 10-fold or more (including any numerical increment
between the listed percentages) as compared to the corresponding non-isotopically
enriched compound.
[0289] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having edema, e.g., lymphedema, or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to reduce
the pill burden, e.g., effect a pill burden of less than nine (9) capsules per day
(TID dosing) of the compound or a metabolite thereof, during the treatment of the
disorder as compared to the corresponding non-isotopically enriched compound.
[0290] In certain embodiments, the pill burden of the compounds as disclosed herein, is
decreased by greater than about 2%, greater than about 5%, greater than about 10%,
greater than about 15%, greater than about 20%, greater than about 25%, greater than
about 30%, greater than about 40%, or by greater than about 50% (including any numerical
increment between the listed percentages) as compared to the corresponding non-isotopically
enriched compound.
[0291] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having edema, e.g., lymphedema, or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to effect
an increased patient tolerability of the compound or a metabolite thereof, during
the treatment of the disorder as compared to the corresponding non-isotopically enriched
compound. In some embodiments, the patient tolerability is increased by altering the
pharmacokinetics, e.g., by increasing the bioavailability (so as to use a lower dose)
and/or by extending the half-life of the compound and/or by other means to reduce
the side effects of pirfenidone.
[0292] In certain embodiments, the patient tolerability of the compounds as disclosed herein,
or metabolites thereof, is increased by greater than about 2%, greater than about
5%, greater than about 10%, greater than about 15%, greater than about 20%, greater
than about 25%, greater than about 30%, greater than about 40%, by greater than about
50%, by greater than about 60%, by greater than about 70%, by greater than about 80%,
by greater than about 90%, or by greater than about 100% (including any numerical
increment between the listed percentages) as compared to the corresponding non-isotopically
enriched compound. In certain embodiments, the patient tolerability of the compounds
as disclosed herein, or metabolites thereof, is increased by about 1.5-fold, increased
by about 2-fold, greater than about 2-fold, greater than about 3-fold, greater than
about 4-fold, greater than about greater than about 5-fold, greater than about 10-fold
or more (including any numerical increment between the listed percentages) as compared
to the corresponding non-isotopically enriched compound.
[0293] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having edema, e.g., lymphedema, or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to effect
a lower efficacious dose per dosage of the compound or a metabolite thereof, during
the treatment of the disorder as compared to the corresponding non-isotopically enriched
compound.
[0294] In certain embodiments, the efficacious dose per dosage of the compounds as disclosed
herein, or metabolites thereof, is decreased by greater than about 2%, greater than
about 5%, greater than about 10%, greater than about 15%, greater than about 20%,
greater than about 25%, greater than about 30%, greater than about 40%, by greater
than about 50%, by greater than about 60%, by greater than about 70%, by greater than
about 80%, by greater than about 90%, or by greater than about 100% (including any
numerical increment between the listed percentages) as compared to the corresponding
non-isotopically enriched compound. In certain embodiments, the efficacious dose per
dosage of the compounds as disclosed herein, or metabolites thereof, is decreased
by about 1.5-fold, decreased by about 2-fold, greater than about 2-fold, greater than
about 3-fold, greater than about 4-fold, greater than about greater than about 5-fold,
greater than about 10-fold or more (including any numerical increment between the
listed percentages) as compared to the corresponding non-isotopically enriched compound.
[0295] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having edema, e.g., lymphedema, or for preventing such disorder in a
subject prone to the disorder; comprising administering to the subject a therapeutically
effective amount of a deuterium-enriched pirfenidone compound as disclosed herein,
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to increase
the bioavailability per dosage of the compound or a metabolite thereof, during the
treatment of the disorder as compared to the corresponding non-isotopically enriched
compound.
[0296] In certain embodiments, the bioavailability per dosage of the compounds as disclosed
herein, or metabolites thereof, is increased by greater than about 2%, greater than
about 5%, greater than about 10%, greater than about 15%, greater than about 20%,
greater than about 25%, greater than about 30%, greater than about 40%, by greater
than about 50%, by greater than about 60%, by greater than about 70%, by greater than
about 80%, by greater than about 90%, or by greater than about 100% (including any
numerical increment between the listed percentages) as compared to the corresponding
non-isotopically enriched compound. In certain embodiments, the bioavailability per
dosage of the compounds as disclosed herein, or metabolites thereof, is increased
by about 1.5-fold, decreased by about 2-fold, greater than about 2-fold, greater than
about 3-fold, greater than about 4-fold, greater than about greater than about 5-fold,
greater than about 10-fold or more (including any numerical increment between the
listed percentages) as compared to the corresponding non-isotopically enriched compound.
[0297] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having or suspected of having edema, e.g., lymphedema, or for preventing
such disorder in a subject prone to the disorder; comprising administering to the
subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound
as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof;
so as to affect an increase in systemic exposure of the compound per dosage unit as
compared to the corresponding non-isotopically enriched compound.
[0298] In certain embodiments, the systemic exposure per dosage of the compounds as disclosed
herein, or metabolites thereof, is increased by greater than about 10%, greater than
about 15%, greater than about 20%, greater than about 25%, greater than about 30%,
greater than about 35%, greater than about 40%, greater than about 45%, or by greater
than about 50% (including any numerical increment between the listed percentages)
as compared to the corresponding non-isotopically enriched compound. In one embodiment,
the systemic exposure per dosage of the compounds as disclosed herein is increased
by greater than about 35% as compared to the corresponding non-isotopically enriched
compound. In one embodiment, the systemic exposure per dosage of the compounds as
disclosed herein is increased by about 35% as compared to the corresponding non-isotopically
enriched compound.
[0299] Disclosed herein are methods for treating a subject, including a human, having or
suspected of having or suspected of having edema, e.g., lymphedema, or for preventing
such disorder in a subject prone to the disorder; comprising administering to the
subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound
as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof;
so as to affect an increase in Cmax of the compound per dosage unit as compared to
the corresponding non-isotopically enriched compound.
[0300] In certain embodiments, the Cmax per dosage of the compounds as disclosed herein,
or metabolites thereof, is increased by greater than about 10%, greater than about
15%, greater than about 20%, greater than about 25%, greater than about 30%, greater
than about 35%, greater than about 40%, greater than about 45%, or by greater than
about 50% (including any numerical increment between the listed percentages) as compared
to the corresponding non-isotopically enriched compound. In one embodiment, the Cmax
per dosage of the compounds as disclosed herein is increased by greater than about
25% as compared to the corresponding non-isotopically enriched compound. In one embodiment,
the Cmax per dosage of the compounds as disclosed herein is increased by about 25%
as compared to the corresponding non-isotopically enriched compound.
[0301] In some embodiments, the method treats the disorder while reducing or eliminating
a deleterious change in a diagnostic hepatobiliary function endpoint, as compared
to the corresponding non-isotopically enriched compound, e.g., pirfenidone. Disclosed
herein are methods for treating a subject, including a human, having or suspected
of having edema, e.g., lymphedema, or for preventing such disorder in a subject prone
to the disorder; comprising administering to the subject a therapeutically effective
amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate,
or prodrug thereof; so as to reduce or eliminate a deleterious change in a diagnostic
hepatobiliary function endpoint, as compared to the corresponding non-isotopically
enriched compound. In some embodiments, the diagnostic hepatobiliary function endpoint
is selected from alanine aminotransferase ("ALT"), serum glutamic-pyruvic transaminase
("SGPT"), aspartate aminotransferase ("AST," "SCOT"), ALT/AST ratios, serum aldolase,
alkaline phosphatase ("ALP"), ammonia levels, bilirubin, gamma-glutamyl transpeptidase
("GGTP," "gamma-GTP," "GGT"), leucine aminopeptidase ("LAP"), liver biopsy, liver
ultrasonography, liver nuclear scan, 5'-nucleotidase, and blood protein.In some embodiments,
the disease, disorder, or condition is selected from idiopathic pulmonary fibrosis,
pneumoconiosis, silicosis, chalicosis, asbestosis, anthracosis, lymphedema (primary
and/or secondary), systemic sclerosis (scleroderma) and/or a condition associated
with scleroderma, juvenile systemic sclerosis (J-SSC), interstitial lung disease,
scleroderma interstitial lung disease, focal segmental glomerulosclerosis (FSGS),
diffuse lung disease such as diffuse parenchymal lung disease, diabetic nephropathy,
lupus nephritis, polycystic kidney disease, ANCA vasculitis, membranous nephropathy,
minimal change disease, chronic kidney disease, myocardial fibrosis, keloid scar,
dermatopolymyositis, fibrotic sarcoidosis, medical device or implant rejection (such
as breast capsular contracture), a fatty liver disease such as non-alcoholic steatohepatitis
(NASH), and hepatitis-C fibrosis.
[0302] In some embodiments, the disease, disorder, or condition is selected from idiopathic
pulmonary fibrosis, lymphedema (primary and/or secondary), systemic sclerosis (scleroderma),
juvenile systemic sclerosis (J-SSC), scleroderma interstitial lung disease, or a condition
associated with scleroderma. In some embodiments, the disease, disorder, or condition
is myocardial fibrosis. In some embodiments, the disease, disorder, or condition is
a keloid scar.
[0303] In some embodiments, the disease, disorder, or condition is dermatopolymyositis.
Dermatopolymyositis (also called PM/DM) is a family of myositis disorders that includes
polymyositis and dermatomyositis. In some embodiments, the disease, disorder, or condition
is selected from dermatomyositis, juvenile dermatomyositis polymyositis, and inclusion
body myositis.
[0304] In some embodiments, the disease, disorder, or condition is scleroderma, progressive
systemic sclerosis, mixed connective tissue disease, or CREST syndrome.
[0305] In some embodiments, the disease, disorder, or condition is fibrotic sarcoidosis.
[0306] In some embodiments, the disease, disorder, or condition is surgical implant rejection
such as an immune reaction to an implanted medical device or capsular contracture
such as breast capsular contracture.
[0307] Compounds and combinations of the present invention may be used to treat a variety
of diseases, disorders, and conditions. In some embodiments, the disease, disorder,
or condition is selected from idiopathic pulmonary fibrosis, neurofibromatosis, Hermansky-Pudlak
syndrome, diabetic nephropathy, renal fibrosis, hypertrophic cardiomyopathy (HCM),
hypertension-related nephropathy, glomerulosclerosis (FSGS), radiation-induced fibrosis,
multiple sclerosis (including secondary progressive multiple sclerosis), uterine leiomyomas
(fibroids), alcoholic liver disease (including hepatic steatosis, hepatic fibrosis
and hepatic cirrhosis), keloid scarring, hepatitis C virus (HCV) infection, proliferative
disorders (including angiogenesis-mediated disorders), cancer (including glioma, glioblastoma,
breast cancer, colon cancer, melanoma and pancreatic cancer), fibrotic disorders,
interstitial lung diseases, atrial fibrillation (AF), organ transplant rejection,
and scleroderma and related fibrotic conditions of the skin.
[0308] In some embodiments, the disease, disorder, or condition is diabetic nephropathy,
Kimmelstiel-Wilson disease or syndrome, diabetic kidney disease, diabetic nephritis,
or intercapillary or intracapillary glomerulosclerosis.
[0309] In some embodiments, the method of this invention is used to treat a disease or condition
selected from idiopathic pulmonary fibrosis, neurofibromatosis, Hermansky-Pudlak syndrome,
diabetic nephropathy, renal failure, hypertrophic cardiomyopathy (HCM), glomerulosclerosis
(FSGS), radiation-induced fibrosis, multiple sclerosis, and uterine leiomyomas (fibroids)
in a patient in need thereof.
[0310] In another particular embodiment, the method of the invention is used to treat renal
fibrosis, hepatic fibrosis, uterine leiomyomas, keloid scarring, multiple sclerosis,
radiation-associated fibrosis, organ transplant rejection, or cancer in a patient
in need thereof.
[0311] In still another particular embodiment, the method is used to treat idiopathic pulmonary
fibrosis in a patient in need thereof. In another particular embodiment, the method
of this invention is used to treat secondary progressive multiple sclerosis in a patient
in need thereof. In another particular embodiment, the method of this invention is
used to treat pancreatic cancer in a patient in need thereof. In another more particular
embodiment, the method of this invention is used to treat renal fibrosis in a patient
in need thereof. More particularly the method is used to treat renal fibrosis as the
result of diabetic nephropathy, glomerulopathy/FSGS or hypertension-related nephropathy.
In still another embodiment, the amount of the compound of this invention administered
to treat hepatic fibrosis in a patient in need thereof. Additional diseases, disorders,
and conditions that may be treated in accordance with the present invention include
those described herein and below.
[0312] In some embodiments, the present invention provides a method of treating, preventing,
or ameliorating a disease, disorder, or condition selected from a fibrotic-meditated
disorder, a collagen-mediated disorder, or a fibrotic-mediated and collagen-mediated
disorder, comprising administering to a subject in need thereof an effective amount
of deuterium-enriched pirfenidone or a pharmaceutically acceptable salt thereof. In
some embodiments, the method further comprises administering an effective amount of
an additional therapeutic agent, such as those described herein.
[0313] In some embodiments, the deuterium-enriched pirfenidone is a compound of Formula
I or a pharmaceutically acceptable salt thereof.
[0314] In some embodiments, deuterium-enriched pirfenidone is LYT-100 or a pharmaceutically
acceptable salt thereof.
[0315] In some embodiments, the deuterium-enriched pirfenidone is co-administered with one
or more additional therapeutic agents, such as those described herein.
[0316] In some embodiments, the disease, disorder, or condition is selected from systemic
sclerosis, systemic sclerosis-related pulmonary fibrosis, sarcoidosis, sarcoidosis-related
pulmonary fibrosis, pulmonary fibrosis caused by infection, asbestos-induced pulmonary
fibrosis, silica-induced pulmonary fibrosis, environmentally induced pulmonary fibrosis,
radiation-induced pulmonary fibrosis, lupus-induced pulmonary fibrosis, drug-induced
pulmonary fibrosis, and hypersensitivity pneumonitis, and/or any disorder ameliorated
by modulating fibrosis and/or collagen infiltration into tissues.
[0317] In some embodiments, the disease, disorder, or condition is selected from idiopathic
pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic
kidney disease, endotoxin-induced liver injury after partial hepatectomy or hepatic
ischemia, allograft injury after organ transplantation, cystic fibrosis, atrial fibrilation,
neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease,
mediastinal fibrosis, tuberculosis, spleen fibrosis caused by sickle-cell anemia,
rheumatoid arthritis, and/or any disorder ameliorated by modulating fibrosis and/or
collagen infiltration into tissues.
[0318] In some embodiments, the disease, disorder, or condition is selected from idiopathic
pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic
kidney disease, endotoxin-induced liver injury after partial hepatectomy or hepatic
ischemia, allograft injury after organ transplantation, cystic fibrosis, atrial fibrilation,
neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease,
mediastinal fibrosis, tuberculosis, spleen fibrosis caused by sickle-cell anemia,
and rheumatoid arthritis.
[0319] In some embodiments, the present disclosure relates to the use of deuterium-enriched
pirfenidone to treat or prevent an inflammatory disease, disorder, or condition. In
some embodiments, the deuterium-enriched pirfenidone is LYT-100. In some embodiments,
the present disclosure provides a method of treating or preventing an inflammatory
disease, disorder, or condition, comprising administering to a subject in need thereof
an effective amount of deuterium-enriched pirfenidone. In some embodiments, the deuterium-enriched
pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof.
[0320] In some embodiments, the present disclosure relates to the use of deuterium-enriched
pirfenidone to treat or prevent a fibrotic disease, disorder, or condition. In some
embodiments, the deuterium-enriched pirfenidone is LYT-100. In some embodiments, the
present disclosure provides a method of treating or preventing a fibrotic disease,
disorder, or condition, comprising administering to a subject in need thereof an effective
amount of deuterium-enriched pirfenidone. In some embodiments, the deuterium-enriched
pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof.
[0321] In some embodiments, the present disclosure relates to the use of deuterium-enriched
pirfenidone to treat or prevent idiopathic pulmonary fibrosis. In some embodiments,
the deuterium-enriched pirfenidone is LYT-100.
[0322] In some embodiments, the present disclosure provides a method of treating or preventing
idiopathic pulmonary fibrosis, comprising administering to a subject in need thereof
an effective amount of deuterium-enriched pirfenidone. In some embodiments, the deuterium-enriched
pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof.
[0323] In some embodiments, the disease, disorder, or condition is idiopathic pulmonary
fibrosis (IPF). In some embodiments, the disease, disorder, or condition is chronic
fibrosing alveolitis, fibrosing alveolitis, fibrosing alveolitis lung, fibrosing lung
disease, Hamman-Rich syndrome, or alveolar fibrosis.
[0324] In some embodiments, the disease, disorder, or condition is systemic sclerosis (scleroderma)
and/or a related interstitial lung disease.
[0325] In some embodiments, the disease, disorder, or condition is a childhood interstitial
lung disease (CHILD). In some embodiments, the childhood interstitial lung disease
is selected from a surfactant dysfunction mutation, a childhood lung developmental
disorder such as alveolar capillary dysplasia, a lung growth abnormality, neuroendocrine
cell hyperplasia of infancy (NEHI), pulmonary interstitial glycogenosis (PIG), idiopathic
interstitial pneumonia (such as nonspecific interstitial pneumonia, cryptogenic organizing
pneumonia, acute interstitial pneumonia, desquamative interstitial pneumonia, lymphocytic
interstitial pneumonia), an alveolar hemorrhage syndrome, an aspiration syndrome,
a hypersensitivity pneumonitis, an infectious or postinfectious disease (bronchiolitis
obliterans), eosinophilic pneumonia, pulmonary alveolar proteinosis, pulmonary infiltrates
with eosinophilia, pulmonary lymphatic disorders (lymphangiomatosis, lymphangiectasis),
pulmonary vascular disorders (haemangiomatosis), an interstitial lung disease associated
with systemic disease process (such as connective tissue diseases, histiocytosis,
malignancy-related lung disease, sarcoidosis, storage diseases), or a disorder of
the compromised immune system (such as opportunistic infection, disorders related
to therapeutic intervention, lung and bone marrow transplant-associated lung diseases,
diffuse alveolar damage of unknown cause).
[0326] The various types of childhood interstitial lung diseases (CHILD) can affect many
parts of the lungs, including the alveoli (air sacs), bronchial tubes (airways), and
capillaries.
[0327] In some embodiments, the disease, disorder, or condition is scleroderma and at least
one related condition selected from interstitial lung disease, tightening of the skin,
joint pain, exaggerated response to cold (Raynaud's disease), and heartburn.
[0328] In some embodiments, the disease, disorder, or condition is selected from abnormal
wound healing, a skin ulcer or scar, pulmonary fibrosis, fibrosis of lung, liver,
kidney, or skin, or Dupuytren's contracture.
[0329] In some embodiments, the inflammatory disease is selected from an inflammatory disease
of the liver or one that affects liver function. In some embodiments, the inflammatory
disease is selected from non-alcoholic steatohepatitis (NASH), a fatty liver disease,
or Hepatitis-C fibrosis.
[0330] In some embodiments, a method for the treatment, prevention, or amelioration of one
or more symptoms of a fibrotic-mediated disorder and/or a collagen-mediated disorder
in a subject comprises administering a therapeutically effective amount of a compound
as disclosed herein.
[0331] In some embodiments, the fibrotic-mediated disorder and/or collagen-mediated disorder
is selected from idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis,
renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial
hepatectomy or hepatic ischemia, allograft injury after organ transplantation, cystic
fibrosis, atrial fibrilation, neutropenia, scleroderma, dermatomyositis, cirrhosis,
diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, spleen fibrosis
caused by sickle-cell anemia, and rheumatoid arthritis.
[0332] In some embodiments, the fibrotic-mediated disorder and/or said collagen-mediated
disorder can be lessened, alleviated, or prevented by modulating fibrosis. In some
embodiments, the fibrotic-mediated disorder and/or said collagen-mediated disorder
can be lessened, alleviated, or prevented by modulating collagen infiltration.
[0333] In some embodiments, the treatment and/or prevention methods described herein may
be performed in combination with one or more additional edema or lymphedema treatment
and/or prevention methods known in the art, for example, treatment methods involving
the administration of other therapeutic agents and/or treatment methods involving
surgery, massage, compression therapy, fluid drainage therapy, acupuncture, laser,
or any other suitable treatment methods.
Definitions
[0334] While the terms used herein are believed to be well understood by one of ordinary
skill in the art, definitions are set forth herein to facilitate explanation of the
presently-disclosed subject matter.
[0335] The term "pharmaceutical composition" refers to a preparation that is in such form
as to permit the biological activity of the active ingredient to be effective, and
which contains no additional components that are unacceptably toxic to a subject to
which the composition would be administered. Pharmaceutical compositions can be in
numerous dosage forms, for example, tablet, capsule, liquid, solution, softgel, suspension,
emulsion, syrup, elixir, tincture, film, powder, hydrogel, ointment, paste, cream,
lotion, gel, mousse, foam, lacquer, spray, aerosol, inhaler, nebulizer, ophthalmic
drops, patch, suppository, and/or enema. Pharmaceutical compositions typically comprise
a pharmaceutically acceptable carrier, and can comprise one or more of a buffer (e.g.
acetate, phosphate or citrate buffer), a surfactant (e.g. polysorbate), a stabilizing
agent (e.g. human albumin), a preservative (e.g. benzyl alcohol), a penetration enhancer,
an absorption promoter to enhance bioavailability and/or other conventional solubilizing
or dispersing agents. Choice of dosage form and excipients depends upon the active
agent to be delivered and the disease or disorder to be treated or prevented, and
is routine to one of ordinary skill in the art.
[0336] The term "deuterium enrichment" refers to the percentage of incorporation of deuterium
at a given position in a molecule in the place of hydrogen. For example, deuterium
enrichment of 1% at a given position means that 1% of molecules in a given sample
contain deuterium at the specified position. Because the naturally occurring distribution
of deuterium is about 0.0156%, deuterium enrichment at any position in a compound
synthesized using non-enriched starting materials is about 0.0156%. The deuterium
enrichment can be determined using conventional analytical methods, such as mass spectrometry
and nuclear magnetic resonance spectroscopy.
[0337] The term "is/are deuterium," when used to describe a given variable position in a
molecule or formula, or the symbol "D," when used to represent a given position in
a drawing of a molecular structure, means that the specified position is enriched
with deuterium above the naturally occurring distribution of deuterium. In some embodiments,
deuterium enrichment is of no less than about 1%, no less than about 5%, no less than
about 10%, no less than about 20%, no less than about 50%, no less than about 70%,
no less than about 80%, no less than about 90%, no less than about 98%, or in some
embodiments no less than about 99% of deuterium at the specified position. In some
embodiments, the deuterium enrichment is above 90% at each specified position. In
some embodiments, the deuterium enrichment is above 95% at each specified position.
In some embodiments, the deuterium enrichment is about 99% at each specified position.
[0338] The term "isotopic enrichment" refers to the percentage of incorporation of a less
prevalent isotope of an element at a given position in a molecule in the place of
the more prevalent isotope of the element.
[0339] The term "non-isotopically enriched" refers to a molecule in which the percentages
of the various isotopes are substantially the same as the naturally occurring percentages.
[0340] The term "fibrosis" refers to the development of excessive fibrous connective tissue
within an organ or tissue.
[0341] The term "collagen infiltration" refers to the entry of the connective tissue collagen
into cells or into the extracellular matrix around cells. This occurs in organs and
tissues naturally and under normal circumstances but can occur excessively and accompany
or cause disease.
[0342] The term "collagen-mediated disorder" refers to a disorder that is characterized
by abnormal or undesired collagenic infiltration, that when collagen infiltration
activity is modified, leads to the desired responses depending on the route of administration
and desired end result. A collagen-mediated disorder may be completely or partially
mediated through the modulation of collagen infiltration. In particular, a collagen-mediated
disorder is one in which modulation of collagen infiltration activity results in some
effect on the underlying disorder, e.g., administering a collagen-infiltration modulator
results in some improvement in at least some of the patients being treated.
[0343] The term "fibrotic-mediated disorder" refers to a disorder that is characterized
by abnormal or undesired fibrotic activity, that when fibrosis activity is modified,
leads to the desired responses depending on the route of administration and desired
end result. A fibrosis-mediated disorder may be completely or partially mediated through
the modulation of fibrosis. In particular, a fibrosis-mediated disorder is one in
which modulation of fibrosis activity results in some effect on the underlying disorder,
e.g., administering a fibrosis modulator results in some improvement in at least some
of the patients being treated.
[0344] The terms "fibrosis modulator" or "modulating fibrosis" are meant to be interchangeable
and refer to the ability of a compound disclosed herein to alter the occurrence and/or
amount of fibrosis. A fibrosis modulator may increase the occurrence or level of fibrosis,
may increase or decrease the occurrence and/or amount of fibrosis depending on the
concentration of the compound exposed to the adrenergic receptor, or may decrease
the occurrence and/or amount of fibrosis. Such activation or inhibition may be contingent
on the occurrence of a specific event, such as activation of a signal transduction
pathway, and/or may be manifest only in particular cell types.
[0345] The terms "collagen-infiltration modulator" or "modulating collagen infiltration"
are meant to be interchangeable and refer to the ability of a compound disclosed herein
to alter the occurrence and/or amount of collagen infiltration. A fibrosis modulator
may increase the occurrence or level of collagen infiltration, may increase or decrease
the occurrence and/or amount of collagen infiltration depending on the concentration
of the compound exposed to the adrenergic receptor, or may decrease the occurrence
and/or amount of collagen infiltration. Such activation or inhibition may be contingent
on the occurrence of a specific event, such as activation of a signal transduction
pathway, and/or may be manifest only in particular cell types.
[0346] An "effective amount" of a composition as disclosed herein is an amount sufficient
to carry out a specifically stated purpose. An "effective amount" can be determined
empirically and in a routine manner, in relation to the stated purpose, route of administration,
and dosage form.
[0347] Terms such as "treating" or "treatment" or "to treat" or "alleviating" or "to alleviate"
refer to therapeutic measures that cure, slow down, ameliorate or lessen one or more
symptoms of, halt progression of, and/or ameliorate or lessen a diagnosed pathologic
condition or disorder. Thus, those in need of treatment include those already with
the disorder. In some embodiments, treatment may be administered after one or more
symptoms have developed. In other embodiments, treatment may be administered in the
absence of symptoms. For example, treatment may be administered to a susceptible individual
prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in
light of genetic or other susceptibility factors). Treatment may also be continued
after symptoms have resolved, for example to prevent or delay their recurrence. In
some embodiments, a subject is successfully "treated" for a disease or disorder according
to the methods provided herein if the patient shows, e.g., total, partial, or transient
alleviation or elimination of symptoms associated with the disease or disorder. For
example, "treating edema" can include, but is not limited to, decreasing swelling,
decreasing inflammation, decreasing fibrosis, decreasing pain, increasing range of
motion, decreasing heaviness, decreasing tightness, decreasing skin thickening, and/or
improving lymphatic function.
[0348] "Prevent" or "prevention" refers to prophylactic or preventative measures that obstruct,
delay and/or slow the development of a targeted pathologic condition or disorder or
one or more symptoms of a a targeted pathologic condition or disorder. Thus, those
in need of prevention include those at risk of or susceptible to developing the disorder.
Subjects that are at risk of or susceptible to developing lymphedema include, but
are not limited to, cancer patients undergoing radiation therapy, chemotherapy, and/or
surgical lymph node dissection. In some embodiments, a disease or disorder is successfully
prevented according to the methods provided herein if the patient develops, transiently
or permanently, e.g., fewer or less severe symptoms associated with the disease or
disorder, or a later onset of symptoms associated with the disease or disorder, than
a patient who has not been subject to the methods of the invention.
[0349] An "anti-T cell agent" is a molecule that reduces T cell-mediated inflammation, T
cell activation, T cell differentiation, and/or T cell proliferation. Classes of anti-T
cell agents include calcineurin inhibitors and IL-2 inhibitors. Examples of small
molecule anti-T cell agents include tacrolimus, teriflunomide, leflunomide, cyclosporine,
and pimecrolimus. Examples of macromolecule anti-T cells agents include denileukin
diftitox and Basiliximab.
[0350] An "anti-TGF-β1 agent" is a molecule that inhibits the expression, secretion, activation,
signaling, or activity of transforming growth factor beta 1. Pirfenidone and deuterium-enriched
pirfenidone are examples of small molecule anti-TGF-β1 agents.
[0351] An "anti-angiotensin agent" is a molecule that inhibits the activity of AngI or AngII,
or a molecule that inhibits AngI to AngII conversion (e.g., ACE inhibitor or ACE agonist).
Examples of anti-angiotensin agents include captopril, zofenopril, enalapril, lisinopril,
ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril, cilazapril,
fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan,
fimasartan, diminazene aceturate, xanthenone, and AVE 099.
[0352] Compounds of the present invention include those described generally herein, and
are further illustrated by the classes, subclasses, and species disclosed herein.
As used herein, the following definitions shall apply unless otherwise indicated.
For purposes of this invention, the chemical elements are identified in accordance
with the Periodic Table of the Elements, Handbook of Chemistry and Physics, 98
th Ed. Additionally, general principles of organic chemistry are described in "
Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and
March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith
and J. March, 7th Edition, John Wiley & Sons, 2013, the entire contents of which are hereby incorporated by reference.
[0353] As used herein, the term "pharmaceutically acceptable salt" refers to those salts
which are, within the scope of sound medical judgment, suitable for use in contact
with the tissues of humans and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge
et al., describe pharmaceutically acceptable salts in detail in
J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds
of this invention include those derived from suitable inorganic and organic acids
and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts include
salts of an amino group (or other basic group) formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric
acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric
acid, citric acid, succinic acid, or malonic acid, or by using other methods used
in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate,
butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,
gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate,
2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate,
succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate
salts, and the like.
[0354] Salts derived from appropriate bases include alkali metal, alkaline earth metal,
ammonium and N
+(C
1-4alkyl)
4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium,
potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts
include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations
formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate,
nitrate, loweralkyl sulfonate and aryl sulfonate.
[0355] Unless otherwise stated, structures depicted herein are also meant to include all
isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms
of the structure; for example, the R and S configurations for each asymmetric center,
Z and E double bond isomers, and Z and E conformational isomers. Therefore, single
stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or
conformational) mixtures of the present compounds are within the scope of the invention.
Unless otherwise stated, all tautomeric forms of the compounds of the invention are
within the scope of the invention. Additionally, unless otherwise stated, structures
depicted herein are also meant to include compounds that differ only in the presence
of one or more isotopically enriched atoms. For example, compounds having the present
structures including the replacement of hydrogen by deuterium or tritium, or the replacement
of a carbon by a
13C- or
14C-enriched carbon are within the scope of this invention. Such compounds are useful,
for example, as analytical tools, as probes in biological assays, or as therapeutic
agents in accordance with the present invention.
[0356] Disclosed compounds, as well as pharmaceutically acceptable compositions comprising
a disclosed compound and a pharmaceutically acceptable excipient, adjuvant, diluent,
or carrier, are useful for treating a variety of diseases, disorders, and conditions.
Such diseases, disorders, and conditions include those described herein.
[0357] One of ordinary skill in the art will recognize that each of the therapeutic agents
described herein are known to be associated with treatment of one or more diseases,
disorders, or conditions. Accordingly, it will be understood that, in certain embodiments,
the present invention provides a method of treating a disease, disorder, or condition
in a patient in need thereof, comprising administering to the patient an effective
amount of a disclosed compound, combination of compounds, or pharmaceutical composition
thereof.
Other Active Agents
[0358] In some embodiments, the present invention provides systemic (e.g., IV or oral) or
local (e.g., topical or transdermal) administration of an anti-T cell, anti-TGF-β1,
and/or anti-angiotensin agent, such as tacrolimus, deuterium-enriched pirfenidone,
teriflunomide, leflunomide, or captopril; or a pharmaceutically acceptable salt thereof.
In some embodiments, administration of such a combination improves lymphedema and
lymphatic function, and has a variety of other beneficial biological effects, including
stimulating lymphangiogenesis, when administered to mammalian subj ects. Moreover,
because these agents act at different steps of the fibrosis pathway, in some embodiments,
combinations of anti-T cell, anti-TGF-β1, and/or anti-angiotensin agents are more
effective than administration of a single agent. In some embodiments, the combination
exhibits synergistic effects. In some embodiments, the present invention provides
systemic or local administration of an anti-TGF-β and/or anti-TNF-alpha agent, such
as deuterium-enriched pirfenidone. In some embodiments, disclosed herein are methods
of treating a disease, e.g., edema, that includes administering LYT-100 and pirfenidone,
wherein together LYT-100 and pirfenidone provide an effective amount of active(s)
to treat the disease.
[0359] Tacrolimus is an anti-T cell agent that is FDA approved as a topical formulation
and used to treat cutaneous inflammatory/fibrotic diseases including atopic dermatitis
(
Ruzicka et al., N. Engl. J. Med. 337:816-821 (1997)), psoriasis (
Wang et al., J. Cutan. Med. Surg. 18:8-14 (2014)), and localized scleroderma (
Mancuso et al., Br. J. Dermatol. 152: 180- 182 (2005)). Tacrolimus is a macrolide produced by the soil bacterium
Streptomyces tsukubaensis that is well-tolerated when used for prevention of transplant rejection and treatment
of a variety of autoimmune diseases. It exerts its anti-T cell properties by binding
to FK-506 binding protein 12 (FKBP-12), thus inhibiting calcineurin, and ultimately
decreasing IL-2 expression.
Clipstone et al., Nature 357:695-697 (1992). Because IL-2 is essential for T cell activation and differentiation of CD4
+ T cells, calcineurin inhibitors have profound CD4
+ cell immunosuppressive effects.
Liao et al., Immunity 38: 13-25 (2013);
Rautajoki et al., Ann. Med. 40:322-335 (2008).
[0361] Captopril is an angiotensin-converting enzyme (ACE) inhibitor, approved by the FDA
for oral administration in the treatment of hypertension and certain types of heart
failure and diabetic nephropathy. ACE converts angiotensin I (AngI) to angiotensin
II (AngII) and causes blood vessel constriction, inhibits vasodilatation, and indirectly
regulates intravascular fluid volumes by effects on the renin-angiotensin-system (RAS).
Therefore, inhibition of ACE has been a mainstay therapy for hypertension. More recent
studies have shown that AngII is also a key regulator of fibrosis in a variety of
organ systems, including the kidney, liver, and lung.
Langham et al., Diabetes Care 29:2670-2675 (2006);
Alves de Albuquerque et al., Kidney Intl. 65:846-859 (2004);
Osterreicher et al., Hepatology. 50:929- 938 (2009);
Mak et al., Mol. Ther. 23: 1434-1443 (2015);
Wang et al., Cell Physiol. Biochem. 36:697-711 (2015). The pro-fibrotic effects of AngII are mediated by a number of mechanisms, including
production of reactive oxygen species, production of chemokines and cytokines, increased
expression of adhesion molecules, and regulation of TGF-β expression/activity. In
contrast, AngI has anti-proliferative and anti-fibrotic activities by activating its
cell surface receptor. Mas.
Clarke et al., Int. J. Hypertens. 2012:307315 (2011). As a result, inhibitors of ACE and/or AngII, such as captopril, losartan, and other
similar medications, have been proposed as a potential therapeutic option for fibrotic
disorders of the lung, kidney, and liver.
[0362] In one aspect, the present invention provides a pharmaceutical composition comprising
deuterium enriched pirfenidone in combination with one or more anti-T cell, anti-TGF-β1,
and/or anti-angiotensin agents and/or anti-inflammatory agents.
[0363] In some embodiments, the anti-T cell agent is selected from tacrolimus, teriflunomide,
leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab. In
some embodiments, the anti-TGF-β1 agent or anti-angiotensin agent is selected from
pirfenidone, deuterium-enriched pirfenidone, captopril, zofenopril, enalapril, lisinopril,
ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril, cilazapril,
fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan,
and fimasartan. In some embodiments, the anti-angiotensin agent is an ACE agonist,
for example, an ACE-2 agonist. The composition can be formulated for systemic administration
or for local administration. In some embodiments, the composition is formulated for
topical administration.
[0364] The pharmaceutical composition of the invention can comprise any combination of anti-T
cell, anti-TGF-β1, and/or anti-angiotensin agents.
[0365] In some embodiments, the composition comprises deuterium-enriched pirfenidone, for
example, a compound of Formula I, e.g., a compound listed in Table 1, including e.g.,
LYT-100, and one or more anti-T cell agent(s). In some embodiments, the composition
comprises deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, and one or more anti-T cell
agent(s) selected from tacrolimus, teriflunomide, leflunomide, cyclosporine, pimecrolimus,
denileukin diftitox, and basiliximab. For instance, in some embodiments, the composition
comprises deuterium-enriched pirfenidone, for example a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, and tacrolimus. In another
example, in some embodiments, the composition comprises deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, and teriflunomide.
[0366] In some embodiments, the composition comprises deuterium-enriched pirfenidone, for
example, a compound of Formula I, e.g., a compound listed in Table 1, including e.g.,
LYT-100, and one or more anti-TGF-β1 agent(s). Non-limiting examples of anti-TGF-β1
agent(s) include LY550410 and LY580276, SB-505124, or galunisertib (LY2157299 Monohydrate),
or deuterium-enriched pirfenidone, e.g., as described herein, e.g., other than LYT-100.
In some embodiments, the composition comprises deuterium-enriched pirfenidone, for
example, a compound of Formula I, e.g., a compound listed in Table 1, including, e.g.,
LYT-100, and one or more anti-TGF-β1 agent(s) selected from LY550410 and LY580276,
SB-505124, or galunisertib (LY2157299 Monohydrate) or deuterium-enriched pirfenidone,
e.g., as described herein, e.g., other than LYT-100. In some embodiments, the composition
comprises deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including, e.g., LYT-100, and a second type of deuterium-enriched
pirfenidone, e.g., for example, a compound of Formula I, e.g., a compound listed in
Table 1, e.g., other than LYT-100.
[0367] In some embodiments, the composition comprises deuterium-enriched pirfenidone, for
example, a compound of Formula I, e.g., a compound listed in Table 1, including, e.g.,
LYT-100, and one or more anti-angiotensin agent(s). In some embodiments, the composition
comprises deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including, e.g., LYT-100, and one or more anti-angiotensin
agent(s) selected from captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril,
perindopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan,
irbesartan, olmesartan, candesartan, telmisartan, valsartan, fimasartan, diminazene
aceturate, xanthenone, and AVE 099. For instance, in some embodiments, the composition
comprises deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including, e.g., LYT-100, and captopril.
[0368] In some embodiments, the composition comprises deuterium-enriched pirfenidone, for
example, a compound of Formula I, e.g., a compound listed in Table 1, including, e.g.,
LYT-100, and one or more anti-inflammatory agent(s). Non-limiting examples of anti-inflammatory
agents include etodolac, famotidine, fenoprofen, fenoprofen, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol,
nabumetone, naproxen, oxaprozin, piroxicam, sulindac, and tolmetin. Anti-inflammatory
agents also include Cox-2 inhibitors, including but not limited to, celecoxib, apricoxib,
robenacoxib, valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib, rofecoxib,
mavacoxib, and firocoxib. In some embodiments, the composition comprises deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including, e.g., LYT-100, and one or more anti-inflammatory agent(s) selected from
etodolac, famotidine, fenoprofen, fenoprofen, flurbiprofen, ibuprofen, indomethacin,
ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone,
naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, apricoxib, robenacoxib,
valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib, rofecoxib, mavacoxib, and
firocoxib. For instance, in some embodiments, the composition comprises deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including, e.g., LYT-100, and ibuprofen.
[0369] In some embodiments, the composition comprises deuterium-enriched pirfenidone, for
example, a compound of Formula I, e.g., a compound listed in Table 1, including, e.g.,
LYT-100, one or more anti-T cell agent(s) and optionally one or more anti-angiotensin
agent(s). In some embodiments, the composition comprises deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including,
e.g., LYT-100, and one or more anti-T cell agent(s) selected from tacrolimus, teriflunomide,
leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab and
optionally one or more anti-angiotensin agent(s). In some embodiments, the one or
more anti-angiotensin agent(s) is selected from captopril, zofenopril, enalapril,
lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril,
cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan,
valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE 099. For instance,
in some embodiments, the composition comprises deuterium-enriched pirfenidone, for
example, a compound of Formula I, e.g., a compound listed in Table 1, including, e.g.,
LYT-100, and tacrolimus and one or more anti-angiotensin agent(s), e.g., captopril.
In another example, in some embodiments, the composition comprises deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including, e.g., LYT-100, teriflunomide and one or more anti-angiotensin agent(s),
e.g., captopril.
[0370] In some embodiments, the composition comprises deuterium-enriched pirfenidone, for
example, a compound of Formula I, e.g., a compound listed in Table 1, including, e.g.,
LYT-100, one or more anti-T cell agent(s) and optionally one or more anti-inflammatory
agent(s). In some embodiments, the composition comprises deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including,
e.g., LYT-100, and one or more anti-T cell agent(s) selected from tacrolimus, teriflunomide,
leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab and
one or more anti-inflammatory agent(s). In some embodiments, the one or more anti-inflammatory
agent(s) is selected from etodolac, famotidine, fenoprofen, fenoprofen, flurbiprofen,
ibuprofen, indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam,
misoprostol, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib,
apricoxib, robenacoxib, valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib,
rofecoxib, mavacoxib, and firocoxib. For instance, in some embodiments, the composition
comprises deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including, e.g., LYT-100, tacrolimus, and ibuprofen.
In another example, in some embodiments, the composition comprises deuterium-enriched
pirfenidone , for example, a compound of Formula I, e.g., a compound listed in Table
1, including, e.g., LYT-100, and teriflunomide, and ibuprofen.
[0371] In some embodiments, the composition comprises deuterium-enriched pirfenidone, for
example, a compound of Formula I, e.g., a compound listed in Table 1, including, e.g.,
LYT-100, one or more anti-TGF-β1 agent(s) and optionally one or more anti-angiotensin
agent(s). In some embodiments, the composition comprises deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including,
e.g., LYT-100, and one or more anti-TGF-β1 agent(s) selected from LY550410, LY580276,
SB-505124, galunisertib (LY2157299 Monohydrate) , and deuterium-enriched pirfenidone,
e.g., as described herein, e.g., other than LYT-100, and optionally one or more anti-angiotensin
agent(s). In some embodiments, the anti-angiotensin agent is selected from captopril,
zofenopril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril,
trandolapril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan,
telmisartan, valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE 099.
For instance, in some embodiments, the composition comprises deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including,
e.g., LYT-100, and one or more anti-TGF-β1 agent(s), e.g., a second form of deuterated
pirfenidone, e.g., other than LYT-100, and one or more anti-angiotensin agent(s),
e.g., captopril.
[0372] In some embodiments, the composition comprises deuterium-enriched pirfenidone, for
example, a compound of Formula I, e.g., a compound listed in Table 1, including, e.g.,
LYT-100, one or more anti-TGF-β1 agent(s) and optionally one or more anti-inflammatory
agent(s). In some embodiments, the composition comprises deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including,
e.g., LYT-100, and one or more anti-TGF-β1 agent(s) selected from LY550410, LY580276,
SB-505124, (LY2157299 Monohydrate) , and deuterium-enriched pirfenidone, e.g., as
described herein, e.g., other than LYT-100, and one or more anti-inflammatory agent(s).
In some embodiments, the one or more anti-inflammatory agent(s) are selected from
etodolac, famotidine, fenoprofen, fenoprofen, flurbiprofen, ibuprofen, indomethacin,
ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone,
naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, apricoxib, robenacoxib,
valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib, rofecoxib, mavacoxib, and
firocoxib. For instance, in some embodiments, the composition comprises deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including, for example, a compound of Formula I, e.g., a compound listed in Table
1, including, e.g., LYT-100, one or more anti-TGF-β1 agent(s), e.g., a deuterium enricher
pirfendone described herein, e.g., other than LYT-100, and ibuprofen.
[0373] In some embodiments, the composition comprises deuterium-enriched pirfenidone, for
example, a compound of Formula I, e.g., a compound listed in Table 1, including e.g.,
LYT-100, one or more anti-T cell agent(s) and optionally an anti-angiotensin agent.
In some embodiments, the composition comprises deuterium-enriched pirfenidone, for
example, a compound of Formula I, e.g., a compound listed in Table 1, including e.g.,
LYT-100, and one or more anti-T cell agent(s) selected from tacrolimus, teriflunomide,
leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab. In
some embodiments, the anti-angiotensin agent is selected from captopril, zofenopril,
enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril,
cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan,
valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE 099. For instance,
in some embodiments, the composition comprises deuterium-enriched pirfenidone , for
example,e.g., a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, tacrolimus and optionally captopril. In some embodiments, the composition
comprises deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, teriflunomide and optionally
captopril.
[0374] The aforementioned pharmaceutical compositions or combinations of two or more therapeutic
agents may be used in treating a disease, disorder, or condition, such as those described
below.
Treatment of Diseases, Disorders, and Conditions with Compounds and Combinations of
the Present Invention
[0375] In one aspect, the present invention relates to the use of a deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
for example, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including,
e.g., LYT-100, in combination with one or more agents selected from anti-TGF-β1 agent,
an anti-T cell agent and/or anti-angiotensin agent to treat a disease, disorder, or
condition such as edema, fibrotic disease, or an inflammatory disorder. In one aspect,
the present disclosure relates to the use of deuterated pirfenidone ,e.g., a compound
of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100, in combination
with an anti-inflammatory and/or anti-fibrotic therapeutic agent to treat a disease,
disorder, or condition such as edema, fibrotic disease, or an inflammatory disorder.
[0376] I Provided herein are methods for the treatment, prevention, and/or amelioration
of a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
in combination with one or more anti-T cell agent(s), anti-TGF-β1, anti-angiotensin
agents, and/or anti-inflammatory agents. In one aspect, the present invention relates
to methods for the treatment, prevention, and/or amelioration of edema, e.g., lymphedema
comprising administering to a subject in need thereof a deuterium-enriched pirfenidone
compound, for example, a compound of Formula I, e.g., a compound listed in Table 1,
including e.g., LYT-100 in combination with one or more anti-T cell agent(s), anti-TGF-β1,
anti-angiotensin agents, and/or anti-inflammatory agents. In one aspect, the present
invention relates to methods for treatment, prevention, and/or amelioration of one
or more symptoms of edema, e.g., lymphedema comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100 in combination
with one or more anti-T cell agent(s), anti-TGF-β1, anti-angiotensin agents, and/or
anti-inflammatory agents. In one aspect, the present invention relates to methods
for treatment, prevention, and/or amelioration of Idiopathic Pulmonary Fibrosis (IPF)
and/or one or more symptoms of IPF, comprising administering to a subject in need
thereof a deuterium-enriched pirfenidone compound, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100 in combination with
one or more anti-T cell agent(s), anti-TGF-β1, and/or anti-angiotensin agents.
[0377] Provided herein are methods for the treatment, prevention, and/or amelioration of
a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
in combination with one or more anti-T cell agent(s). In some embodiments, the methods
for the treatment, prevention, and/or amelioration of a fibrotic-mediated disorder
and/or a collagen-mediated disorder comprise administering to a subject in need thereof
a deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g., a compound
listed in Table 1, including e.g., LYT-100, and one or more anti-T cell agent(s) selected
from tacrolimus, teriflunomide, leflunomide, cyclosporine, pimecrolimus, denileukin
diftitox, and basiliximab. For instance, in some embodiments, the methods for the
treatment, prevention, and/or amelioration of a fibrotic-mediated disorder and/or
a collagen-mediated disorder comprise administering to a subject in need thereof a
deuterium-enriched pirfenidone, for example a compound of Formula I, e.g., a compound
listed in Table 1, including e.g., LYT-100, and tacrolimus. In another example, in
some embodiments, the methods for the treatment, prevention, and/or amelioration of
a fibrotic-mediated disorder and/or a collagen-mediated disorder comprise administering
to a subject in need thereof a deuterium-enriched pirfenidone, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100, and teriflunomide..
[0378] Provided herein are methods for the treatment, prevention, and/or amelioration of
edema, e.g., lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including e.g., LYT-100 in combination with one or more anti-T cell agent(s).
In some embodiments, the methods for the treatment, prevention, and/or amelioration
of edema, e.g., lymphedema comprise administering to a subject in need thereof deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including e.g., LYT-100, and one or more anti-T cell agent(s) selected from tacrolimus,
teriflunomide, leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab.
For instance, in some embodiments, the methods for the treatment, prevention, and/or
amelioration of edema, e.g., lymphedema comprise administering to a subject in need
thereof deuterium-enriched pirfenidone, for example a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, and tacrolimus. In another
example, in some embodiments, the methods for the treatment, prevention, and/or amelioration
of edema, e.g., lymphedema comprise administering to a subject in need thereof deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including e.g., LYT-100, and teriflunomide.
[0379] Provided herein are methods for treatment, prevention, and/or amelioration of one
or more symptoms of edema, e.g., lymphedema comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100 in combination
with one or more anti-T cell agent(s). In some embodiments, the methods for treatment,
prevention, and/or amelioration of one or more symptoms of edema, e.g., lymphedema
comprise administering to a subject in need thereof a deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, and one or more anti-T cell agent(s) selected from tacrolimus, teriflunomide,
leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab. For
instance, in some embodiments, the methods for treatment, prevention, and/or amelioration
of one or more symptoms of edema, e.g., lymphedema comprise administering to a subject
in need thereof a deuterium-enriched pirfenidone, for example a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, and tacrolimus. In
another example, in some embodiments, the methods for treatment, prevention, and/or
amelioration of one or more symptoms of edema, e.g., lymphedema comprise administering
to a subject in need thereof a deuterium-enriched pirfenidone, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100, and teriflunomide.
[0380] Provided herein are methods for treatment, prevention, and/or amelioration of Idiopathic
Pulmonary Fibrosis (IPF) and/or one or more symptoms of IPF, comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100
in combination with one or more anti-T cell agent(s). In some embodiments, the methods
for treatment, prevention, and/or amelioration of Idiopathic IPF and/or one or more
symptoms of IPF, comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including e.g., LYT-100, and one or more anti-T cell agent(s) selected from tacrolimus,
teriflunomide, leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab.
For instance, in some embodiments, the methods for treatment, prevention, and/or amelioration
of IPF and/or one or more symptoms of IPF comprise administering to a subject in need
thereof a deuterium-enriched pirfenidone, for example a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, and tacrolimus. In another
example, in some embodiments, the methods for treatment, prevention, and/or amelioration
of IPF and/or one or more symptoms of IPF comprise administering to a subject in need
thereof a deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, and teriflunomide.
[0381] Provided herein are methods for the treatment, prevention, and/or amelioration of
a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100
in combination with one or more anti-TGF-β1 agent(s). In some embodiments, the methods
for the treatment, prevention, and/or amelioration of a fibrotic-mediated disorder
and/or a collagen-mediated disorder comprise administering to a subject in need thereof
a deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g., a compound
listed in Table 1, including e.g., LYT-100, and one or more anti-TGF-β1 agent(s) selected
from LY550410 and LY580276, SB-505124, or galunisertib (LY2157299 Monohydrate) or
deuterium-enriched pirfenidone, e.g., as described herein, for example, a compound
of Formula I, e.g., a compound listed in Table 1, e.g., other than LYT-100. In some
embodiments, the methods for the treatment, prevention, and/or amelioration of a fibrotic-mediated
disorder and/or a collagen-mediated disorder comprise administering to a subject in
need thereof a deuterium-enriched pirfenidone, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, and a second type
of deuterium-enriched pirfenidone, e.g., for example, a compound of Formula I, e.g.,
a compound listed in Table 1, e.g., other than LYT-100.
[0382] Provided herein are methods for the treatment, prevention, and/or amelioration of
edema, e.g., lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including e.g., LYT-100, in combination with one or more anti-TGF-β1 agent(s).
In some embodiments, the methods for the treatment, prevention, and/or amelioration
of edema, e.g., lymphedema comprise administering to a subject in need thereof deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including e.g., LYT-100, and one or more anti-TGF-β1 agent(s) selected from LY550410
and LY580276, SB-505124, galunisertib (LY2157299 Monohydrate), and deuterium-enriched
pirfenidone, e.g., as described herein, e.g., other than LYT-100. In some embodiments,
the methods for the treatment, prevention, and/or amelioration of edema, e.g., lymphedema
comprise administering to a subject in need thereof a deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, and a second type of deuterium-enriched pirfenidone, e.g., for example,
a compound of Formula I, e.g., a compound listed in Table 1, e.g., other than LYT-100.
[0383] Provided herein are methods for treatment, prevention, and/or amelioration of one
or more symptoms of edema, e.g., lymphedema comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100 in combination
with one or more anti-TGF-β1 agent(s). In some embodiments, the methods for treatment,
prevention, and/or amelioration of one or more symptoms of edema, e.g., lymphedema
comprise administering to a subject in need thereof a deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, and one or more anti-TGF-β1 agent(s) selected from LY550410 and LY580276,
SB-505124, or galunisertib (LY2157299 Monohydrate) or deuterium-enriched pirfenidone,
e.g., as described herein, other than LYT-100. In some embodiments, the methods for
treatment, prevention, and/or amelioration of one or more symptoms of edema, e.g.,
lymphedema comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including e.g., LYT-100, and a second type of deuterium-enriched pirfenidone, e.g.,
for example, a compound of Formula I, e.g., a compound listed in Table 1, e.g., other
than LYT-100.
[0384] Provided herein are methods for treatment, prevention, and/or amelioration of IPF
and/or one or more symptoms of IPF, comprising administering to a subject in need
thereof a deuterium-enriched pirfenidone compound, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100 in combination with
one or more anti-TGF-β1 agent(s). In some embodiments, the methods for treatment,
prevention, and/or amelioration of IPF and/or one or more symptoms of IPF, comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
and one or more anti-TGF-β1 agent(s) selected from LY550410 and LY580276, SB-505124,
or galunisertib (LY2157299 Monohydrate) or deuterium-enriched pirfenidone, e.g., as
described herein, e.g., other than LYT-100. In some embodiments, the methods for treatment,
prevention, and/or amelioration of IPF and/or one or more symptoms of IPF, comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
and a second type of deuterium-enriched pirfenidone, e.g., for example, a compound
of Formula I, e.g., a compound listed in Table 1, e.g., other than LYT-100.
[0385] Provided herein are methods for the treatment, prevention, and/or amelioration of
a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100
in combination with an anti-angiotensin agent. In some embodiments, the methods for
the treatment, prevention, and/or amelioration of a fibrotic-mediated disorder and/or
a collagen-mediated disorder comprise administering to a subject in need thereof a
deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g., a compound
listed in Table 1, including e.g., LYT-100, and one or more anti-angiotensin agent(s)
selected from captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril, perindopril,
benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan, irbesartan,
olmesartan, candesartan, telmisartan, valsartan, fimasartan, diminazene aceturate,
xanthenone, and AVE 099. For instance, in some embodiments, the methods for the treatment,
prevention, and/or amelioration of a fibrotic-mediated disorder and/or a collagen-mediated
disorder comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including, e.g., LYT-100, and captopril.
[0386] Provided herein are methods for the treatment, prevention, and/or amelioration of
edema, e.g., lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including, e.g., LYT-100 in combination with an anti-angiotensin agent.
In some embodiments, the methods for the treatment, prevention, and/or amelioration
of edema, e.g., lymphedema comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including, e.g., LYT-100, and one or more anti-angiotensin agent(s) selected from
captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril,
imidapril, trandolapril, cilazapril, fosinopril, losartan, irbesartan, olmesartan,
candesartan, telmisartan, valsartan, fimasartan, diminazene aceturate, xanthenone,
and AVE 099. For instance, in some embodiments, the methods for the treatment, prevention,
and/or amelioration of edema, e.g., lymphedema comprise administering to a subject
in need thereof a deuterium-enriched pirfenidone, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including, e.g., LYT-100, and captopril.
[0387] Provided herein are methods for treatment, prevention, and/or amelioration of one
or more symptoms of edema, e.g., lymphedema comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100, in combination
with an anti-angiotensin agent. In some embodiments, the methods for treatment, prevention,
and/or amelioration of one or more symptoms of edema, e.g., lymphedema comprise administering
to a subject in need thereof a deuterium-enriched pirfenidone, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one
or more anti-angiotensin agent(s) selected from captopril, zofenopril, enalapril,
lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril,
cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan,
valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE 099. For instance,
in some embodiments, the methods for treatment, prevention, and/or amelioration of
one or more symptoms of edema, e.g., lymphedema comprise administering to a subject
in need thereof a deuterium-enriched pirfenidone, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, and captopril.
[0388] Provided herein are methods for treatment, prevention, and/or amelioration of IPF
and/or one or more symptoms of IPF, comprising administering to a subject in need
thereof a deuterium-enriched pirfenidone compound, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including, e.g., LYT-100, in combination with
an anti-angiotensin agent. In some embodiments, the methods for treatment, prevention,
and/or amelioration of IPF and/or one or more symptoms of IPF, comprise administering
to a subject in need thereof a deuterium-enriched pirfenidone, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one
or more anti-angiotensin agent(s) selected from captopril, zofenopril, enalapril,
lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril,
cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan,
valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE 099. For instance,
in some embodiments, the methods for treatment, prevention, and/or amelioration of
IPF and/or one or more symptoms of IPF, comprise administering to a subject in need
thereof a deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, and captopril.
[0389] Provided herein are methods for the treatment, prevention, and/or amelioration of
a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100,
in combination with one or more anti-inflammatory agent(s). In some embodiments, the
methods for the treatment, prevention, and/or amelioration of a fibrotic-mediated
disorder and/or a collagen-mediated disorder comprise administering to a subject in
need thereof a deuterium-enriched pirfenidone, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one or more anti-inflammatory
agent(s) selected from etodolac, famotidine, fenoprofen, fenoprofen, flurbiprofen,
ibuprofen, indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam,
misoprostol, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib,
apricoxib, robenacoxib, valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib,
rofecoxib, mavacoxib, and firocoxib. For instance, in some embodiments, the methods
for the treatment, prevention, and/or amelioration of a fibrotic-mediated disorder
and/or a collagen-mediated disorder comprise administering to a subject in need thereof
a deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g., a compound
listed in Table 1, including e.g., LYT-100, and ibuprofen.
[0390] Provided herein are methods for the treatment, prevention, and/or amelioration of
edema, e.g., lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including, e.g., LYT-100, in combination with one or more anti-inflammatory
agent(s). In some embodiments, the methods for the treatment, prevention, and/or amelioration
of edema, e.g., lymphedema comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including e.g., LYT-100, and one or more anti-inflammatory agent(s) selected from
selected from etodolac, famotidine, fenoprofen, fenoprofen, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol,
nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, apricoxib,
robenacoxib, valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib, rofecoxib,
mavacoxib, and firocoxib. For instance, in some embodiments, the methods for the treatment,
prevention, and/or amelioration of edema, e.g., lymphedema comprise administering
to a subject in need thereof a deuterium-enriched pirfenidone, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100, and ibuprofen.
[0391] Provided herein are methods for treatment, prevention, and/or amelioration of one
or more symptoms of edema, e.g., lymphedema comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100, in combination
with one or more anti-inflammatory agent(s). In some embodiments, the methods for
treatment, prevention, and/or amelioration of one or more symptoms of edema, e.g.,
lymphedema comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including e.g., LYT-100, and one or more anti-inflammatory agent(s) selected from
selected from etodolac, famotidine, fenoprofen, fenoprofen, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol,
nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, apricoxib,
robenacoxib, valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib, rofecoxib,
mavacoxib, and firocoxib. For instance, in some embodiments, the methods for treatment,
prevention, and/or amelioration of one or more symptoms of edema, e.g., lymphedema
comprise administering to a subject in need thereof a deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, and ibuprofen.
[0392] Provided herein are methods for treatment, prevention, and/or amelioration of IPF
and/or one or more symptoms of IPF, comprising administering to a subject in need
thereof a deuterium-enriched pirfenidone compound, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including, e.g., LYT-100, in combination with
one or more anti-inflammatory agent(s). In some embodiments, the methods for treatment,
prevention, and/or amelioration of IPF and/or one or more symptoms of IPF, comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
and one or more anti-inflammatory agent(s) selected from selected from etodolac, famotidine,
fenoprofen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,
lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone, naproxen, oxaprozin,
piroxicam, sulindac, tolmetin, celecoxib, apricoxib, robenacoxib, valdecoxib, anitrazafen,
tilmacoxib, flumizole, cimicoxib, rofecoxib, mavacoxib, and firocoxib. For instance,
in some embodiments, the methods for treatment, prevention, and/or amelioration of
IPF and/or one or more symptoms of IPF, comprise administering to a subject in need
thereof a deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, and ibuprofen.
[0393] Provided herein are methods for the treatment, prevention, and/or amelioration of
a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100
in combination with one or more anti-T cell agent(s) and optionally one or more anti-angiotensin
agent(s). In some embodiments, the methods for the treatment, prevention, and/or amelioration
of a fibrotic-mediated disorder and/or a collagen-mediated disorder comprise administering
to a subject in need thereof a deuterium-enriched pirfenidone, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one
or more anti-T cell agent(s) selected from tacrolimus, teriflunomide, leflunomide,
cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab and optionally an
anti-angiotensin agent. In some embodiments, the one or more anti-angiotensin agent(s)
is selected from captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril,
perindopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan,
irbesartan, olmesartan, candesartan, telmisartan, valsartan, fimasartan, diminazene
aceturate, xanthenone, and AVE 099. For instance, in some embodiments, the methods
for the treatment, prevention, and/or amelioration of a fibrotic-mediated disorder
and/or a collagen-mediated disorder comprise administering to a subject in need thereof
a deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g., a compound
listed in Table 1, including e.g., LYT-100, and tacrolimus and an anti-angiotensin
agent, e.g., captopril. In another example, in some embodiments, the methods for the
treatment, prevention, and/or amelioration of a fibrotic-mediated disorder and/or
a collagen-mediated disorder comprise administering to a subject in need thereof a
deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g., a compound
listed in Table 1, including e.g., LYT-100, teriflunomide and an anti-angiotensin
agent, e.g., captopril.
[0394] Provided herein are methods for the treatment, prevention, and/or amelioration of
edema, e.g., lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including, e.g., LYT-100 in combination with one or more anti-T cell agent(s)
and optionally one or more anti-angiotensin agent(s). In some embodiments, the methods
for the treatment, prevention, and/or amelioration of edema, e.g., lymphedema comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
and one or more anti-T cell agent(s) selected from tacrolimus, teriflunomide, leflunomide,
cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab and optionally an
anti-angiotensin agent. In some embodiments, the one or more anti-angiotensin agent(s)
is selected from captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril,
perindopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan,
irbesartan, olmesartan, candesartan, telmisartan, valsartan, fimasartan, diminazene
aceturate, xanthenone, and AVE 099. For instance, in some embodiments, the methods
for the treatment, prevention, and/or amelioration of edema, e.g., lymphedema comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
and tacrolimus and an anti-angiotensin agent, e.g., captopril. In another example,
in some embodiments, the methods for the treatment, prevention, and/or amelioration
of edema, e.g., lymphedema comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including e.g., LYT-100, teriflunomide and an anti-angiotensin agent, e.g., captopril.
[0395] Provided herein are methods for treatment, prevention, and/or amelioration of one
or more symptoms of edema, e.g., lymphedema comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100 in combination
with one or more anti-T cell agent(s) and optionally one or more anti-angiotensin
agent(s). In some embodiments, the methods for treatment, prevention, and/or amelioration
of one or more symptoms of edema, e.g., lymphedema comprise administering to a subject
in need thereof a deuterium-enriched pirfenidone, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one or more anti-T
cell agent(s) selected from tacrolimus, teriflunomide, leflunomide, cyclosporine,
pimecrolimus, denileukin diftitox, and basiliximab and optionally an anti-angiotensin
agent. In some embodiments, the one or more anti-angiotensin agent(s) is selected
from captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril, perindopril,
benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan, irbesartan,
olmesartan, candesartan, telmisartan, valsartan, fimasartan, diminazene aceturate,
xanthenone, and AVE 099. For instance, in some embodiments, the methods for treatment,
prevention, and/or amelioration of one or more symptoms of edema, e.g., lymphedema
comprise administering to a subject in need thereof a deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, and tacrolimus and an anti-angiotensin agent, e.g., captopril. In another
example, in some embodiments, the methods for treatment, prevention, and/or amelioration
of one or more symptoms of edema, e.g., lymphedema comprise administering to a subject
in need thereof a deuterium-enriched pirfenidone, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, teriflunomide and
an anti-angiotensin agent, e.g., captopril.
[0396] Provided herein are methods for treatment, prevention, and/or amelioration of IPF
and/or one or more symptoms of IPF comprising administering to a subject in need thereof
a deuterium-enriched pirfenidone compound, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including, e.g., LYT-100 in combination with one or
more anti-T cell agent(s) and optionally one or more anti-angiotensin agent(s). In
some embodiments, the methods for treatment, prevention, and/or amelioration of IPF
and/or one or more symptoms of IPF comprise administering to a subject in need thereof
a deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g., a compound
listed in Table 1, including e.g., LYT-100, and one or more anti-T cell agent(s) selected
from tacrolimus, teriflunomide, leflunomide, cyclosporine, pimecrolimus, denileukin
diftitox, and basiliximab and optionally an anti-angiotensin agent. In some embodiments,
the one or more anti-angiotensin agent(s) is selected from captopril, zofenopril,
enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril,
cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan,
valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE 099. For instance,
in some embodiments, the methods for treatment, prevention, and/or amelioration of
IPF and/or one or more symptoms of IPF comprise administering to a subject in need
thereof a deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, and tacrolimus and an anti-angiotensin
agent, e.g., captopril. In another example, in some embodiments, the methods for treatment,
prevention, and/or amelioration of IPF and/or one or more symptoms of IPF comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
teriflunomide and an anti-angiotensin agent, e.g., captopril.
[0397] Provided herein are methods for the treatment, prevention, and/or amelioration of
a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100,
in combination with one or more anti-T cell agent(s) and optionally one or more anti-inflammatory
agent(s). In some embodiments, the methods for the treatment, prevention, and/or amelioration
of a fibrotic-mediated disorder and/or a collagen-mediated disorder comprise administering
to a subject in need thereof a deuterium-enriched pirfenidone, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one
or more anti-T cell agent(s) selected from tacrolimus, teriflunomide, leflunomide,
cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab and one or more anti-inflammatory
agent(s). In some embodiments, the one or more anti-inflammatory agent(s) is selected
from etodolac, famotidine, fenoprofen, fenoprofen, flurbiprofen, ibuprofen, indomethacin,
ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone,
naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, apricoxib, robenacoxib,
valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib, rofecoxib, mavacoxib, and
firocoxib. For instance, in some embodiments, the methods for the treatment, prevention,
and/or amelioration of a fibrotic-mediated disorder and/or a collagen-mediated disorder
comprise administering to a subject in need thereof a deuterium-enriched pirfenidone
, for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, tacrolimus, and ibuprofen. In another example, in some embodiments,
the methods for the treatment, prevention, and/or amelioration of a fibrotic-mediated
disorder and/or a collagen-mediated disorder comprise administering to a subject in
need thereof a deuterium-enriched pirfenidone , for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, and teriflunomide,
and ibuprofen.
[0398] Provided herein are methods for the treatment, prevention, and/or amelioration of
edema, e.g., lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including, e.g., LYT-100, in combination with one or more anti-T cell
agent(s) and optionally one or more anti-inflammatory agent(s). In some embodiments,
the methods for the treatment, prevention, and/or amelioration of edema, e.g., lymphedema
comprise administering to a subject in need thereof a deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, and one or more anti-T cell agent(s) selected from tacrolimus, teriflunomide,
leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab and
one or more anti-inflammatory agent(s). In some embodiments, the one or more anti-inflammatory
agent(s) is selected from etodolac, famotidine, fenoprofen, fenoprofen, flurbiprofen,
ibuprofen, indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam,
misoprostol, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib,
apricoxib, robenacoxib, valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib,
rofecoxib, mavacoxib, and firocoxib. For instance, in some embodiments, the methods
for the treatment, prevention, and/or amelioration of edema, e.g., lymphedema comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone , for
example, a compound of Formula I, e.g., a compound listed in Table 1, including e.g.,
LYT-100, tacrolimus, and ibuprofen. In another example, in some embodiments, the methods
for the treatment, prevention, and/or amelioration of edema, e.g., lymphedema comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone , for
example, a compound of Formula I, e.g., a compound listed in Table 1, including e.g.,
LYT-100, and teriflunomide, and ibuprofen.
[0399] Provided herein are methods for treatment, prevention, and/or amelioration of one
or more symptoms of edema, e.g., lymphedema comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100, in combination
with one or more anti-T cell agent(s) and optionally one or more anti-inflammatory
agent(s). In some embodiments, the methods for treatment, prevention, and/or amelioration
of one or more symptoms of edema, e.g., lymphedema comprise administering to a subject
in need thereof a deuterium-enriched pirfenidone, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one or more anti-T
cell agent(s) selected from tacrolimus, teriflunomide, leflunomide, cyclosporine,
pimecrolimus, denileukin diftitox, and basiliximab and one or more anti-inflammatory
agent(s). In some embodiments, the one or more anti-inflammatory agent(s) is selected
from etodolac, famotidine, fenoprofen, fenoprofen, flurbiprofen, ibuprofen, indomethacin,
ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone,
naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, apricoxib, robenacoxib,
valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib, rofecoxib, mavacoxib, and
firocoxib. For instance, in some embodiments, the methods for treatment, prevention,
and/or amelioration of one or more symptoms of edema, e.g., lymphedema compriss administering
to a subject in need thereof a deuterium-enriched pirfenidone , for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100, tacrolimus,
and ibuprofen. In another example, in some embodiments, the methods for treatment,
prevention, and/or amelioration of one or more symptoms of edema, e.g., lymphedema
comprise administering to a subject in need thereof a deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, and teriflunomide, and ibuprofen.
[0400] Provided herein are methods for treatment, prevention, and/or amelioration of IPF
and/or one or more symptoms of IPF comprising administering to a subject in need thereof
a deuterium-enriched pirfenidone compound, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including, e.g., LYT-100, in combination with one or
more anti-T cell agent(s) and optionally one or more anti-inflammatory agent(s). In
some embodiments, the methods for treatment, prevention, and/or amelioration of IPF
and/or one or more symptoms of IPF comprise administering to a subject in need thereof
a deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g., a compound
listed in Table 1, including e.g., LYT-100, and one or more anti-T cell agent(s) selected
from tacrolimus, teriflunomide, leflunomide, cyclosporine, pimecrolimus, denileukin
diftitox, and basiliximab and one or more anti-inflammatory agent(s). In some embodiments,
the one or more anti-inflammatory agent(s) is selected from etodolac, famotidine,
fenoprofen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,
lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone, naproxen, oxaprozin,
piroxicam, sulindac, tolmetin, celecoxib, apricoxib, robenacoxib, valdecoxib, anitrazafen,
tilmacoxib, flumizole, cimicoxib, rofecoxib, mavacoxib, and firocoxib. For instance,
in some embodiments, the methods for treatment, prevention, and/or amelioration of
IPF and/or one or more symptoms of IPF comprise administering to a subject in need
thereof a deuterium-enriched pirfenidone , for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, tacrolimus, and ibuprofen.
In another example, in some embodiments, the methods for treatment, prevention, and/or
amelioration of IPF and/or one or more symptoms of IPF comprise administering to a
subject in need thereof a deuterium-enriched pirfenidone , for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100, and teriflunomide,
and ibuprofen.
[0401] Provided herein are methods for the treatment, prevention, and/or amelioration of
a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100,
in combination with one or more anti-TGF-β1 agent(s) and optionally an anti-angiotensin
agent. In some embodiments, the methods for the treatment, prevention, and/or amelioration
of a fibrotic-mediated disorder and/or a collagen-mediated disorder comprise administering
to a subject in need thereof a deuterium-enriched pirfenidone, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one
or more anti-TGF-β1 agent(s) selected from LY550410, LY580276, SB-505124, galunisertib
(LY2157299 Monohydrate) , and deuterium-enriched pirfenidone, e.g., as described herein,
other than LYT-100, and optionally an anti-angiotensin agent. In some embodiments,
the anti-angiotensin agent is selected from captopril, zofenopril, enalapril, lisinopril,
ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril, cilazapril,
fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan,
fimasartan, diminazene aceturate, xanthenone, and AVE 099. For instance, in some embodiments,
the methods for the treatment, prevention, and/or amelioration of a fibrotic-mediated
disorder and/or a collagen-mediated disorder comprise administering to a subject in
need thereof a deuterium-enriched pirfenidone, for example,e.g., a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one or more anti-TGF-β1
agent(s), e.g., a second form of deuterated pirfenidone, e.g., other than LYT-100,
and an anti-angiotensin agent, e.g., captopril.
[0402] Provided herein are methods for the treatment, prevention, and/or amelioration of
edema, e.g., lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including, e.g., LYT-100, in combination with one or more anti-TGF-β1
agent(s) and optionally an anti-angiotensin agent. In some embodiments, the methods
for the treatment, prevention, and/or amelioration of edema, e.g., lymphedema comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
and one or more anti-TGF-β1 agent(s) selected from LY550410, LY580276, SB-505124,
galunisertib (LY2157299 Monohydrate) , and deuterium-enriched pirfenidone, e.g., as
described herein, other than LYT-100, and optionally an anti-angiotensin agent. In
some embodiments, the anti-angiotensin agent is selected from captopril, zofenopril,
enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril,
cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan,
valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE 099. For instance,
in some embodiments, the methods for the treatment, prevention, and/or amelioration
of edema, e.g., lymphedema comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone , for example,e.g., a compound of Formula I, e.g., a compound listed in
Table 1, including e.g., LYT-100, and one or more anti-TGF-β1 agent(s), e.g., a second
form of deuterated pirfenidone, e.g., other than LYT-100, and an anti-angiotensin
agent, e.g., captopril.
[0403] Provided herein are methods for treatment, prevention, and/or amelioration of one
or more symptoms of edema, e.g., lymphedema comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100, in combination
with one or more anti-TGF-β1 agent(s) and optionally an anti-angiotensin agent. In
some embodiments, the methods for treatment, prevention, and/or amelioration of one
or more symptoms of edema, e.g., lymphedema comprise administering to a subject in
need thereof a deuterium-enriched pirfenidone, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one or more anti-TGF-β1
agent(s) selected from LY550410, LY580276, SB-505124, galunisertib (LY2157299 Monohydrate)
, and deuterium-enriched pirfenidone, e.g., as described herein, other than LYT-100,
and optionally an anti-angiotensin agent. In some embodiments, the anti-angiotensin
agent is selected from captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril,
perindopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan,
irbesartan, olmesartan, candesartan, telmisartan, valsartan, fimasartan, diminazene
aceturate, xanthenone, and AVE 099. For instance, in some embodiments, the methods
for treatment, prevention, and/or amelioration of one or more symptoms of edema, e.g.,
lymphedema comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone , for example,e.g., a compound of Formula I, e.g., a compound listed in
Table 1, including e.g., LYT-100, and one or more anti-TGF-β1 agent(s), e.g., a second
form of deuterated pirfenidone, e.g., other than LYT-100, and an anti-angiotensin
agent, e.g., captopril.
[0404] Provided herein are methods for treatment, prevention, and/or amelioration of IPF
and/or one or more symptoms of IPF comprising administering to a subject in need thereof
a deuterium-enriched pirfenidone compound, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including, e.g., LYT-100, in combination with one or
more anti-TGF-β1 agent(s) and optionally an anti-angiotensin agent. In some embodiments,
the methods for treatment, prevention, and/or amelioration of IPF and/or one or more
symptoms of IPF comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including e.g., LYT-100, and one or more anti-TGF-β1 agent(s) selected from LY550410,
LY580276, SB-505124, galunisertib (LY2157299 Monohydrate) , and deuterium-enriched
pirfenidone, e.g., as described herein, other than LYT-100, and optionally an anti-angiotensin
agent. In some embodiments, the anti-angiotensin agent is selected from captopril,
zofenopril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril,
trandolapril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan,
telmisartan, valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE 099.
For instance, in some embodiments, the methods for treatment, prevention, and/or amelioration
of IPF and/or one or more symptoms of IPF comprise administering to a subject in need
thereof a deuterium-enriched pirfenidone , for example,e.g., a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one or more anti-TGF-β1
agent(s), e.g., a second form of deuterated pirfenidone, e.g., other than LYT-100,
and an anti-angiotensin agent, e.g., captopril.
[0405] Provided herein are methods for the treatment, prevention, and/or amelioration of
a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100,
in combination with one or more anti-TGF-β1 agent(s) and optionally one or more anti-inflammatory
agent(s). In some embodiments, the methods for the treatment, prevention, and/or amelioration
of a fibrotic-mediated disorder and/or a collagen-mediated disorder comprise administering
to a subject in need thereof a deuterium-enriched pirfenidone, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one
or more anti-TGF-β1 agent(s) selected from LY550410, LY580276, SB-505124, (LY2157299
Monohydrate) , and deuterium-enriched pirfenidone, e.g., as described herein, other
than LYT-100, and one or more anti-inflammatory agent(s). In some embodiments, the
one or more anti-inflammatory agent(s) are selected from selected from etodolac, famotidine,
fenoprofen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,
lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone, naproxen, oxaprozin,
piroxicam, sulindac, tolmetin, celecoxib, apricoxib, robenacoxib, valdecoxib, anitrazafen,
tilmacoxib, flumizole, cimicoxib, rofecoxib, mavacoxib, and firocoxib. For instance,
in some embodiments, the methods for the treatment, prevention, and/or amelioration
of a fibrotic-mediated disorder and/or a collagen-mediated disorder comprise administering
to a subject in need thereof a deuterium-enriched pirfenidone, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including , for example,e.g., a
compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
one or more anti-TGF-β1 agent(s), e.g., a deuterium enricher pirfendone described
herein other than LYT-100, and ibuprofen.
[0406] Provided herein are methods for the treatment, prevention, and/or amelioration of
edema, e.g., lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including, e.g., LYT-100, in combination with one or more anti-TGF-β1
agent(s) and optionally one or more anti-inflammatory agent(s). In some embodiments,
the methods for the treatment, prevention, and/or amelioration of edema, e.g., lymphedema
comprise administering to a subject in need thereof a deuterium-enriched pirfenidone,
for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, and one or more anti-TGF-β1 agent(s) selected from LY550410, LY580276,
SB-505124, (LY2157299 Monohydrate) , and deuterium-enriched pirfenidone, e.g., as
described herein, other than LYT-100, and one or more anti-inflammatory agent(s).
In some embodiments, the one or more anti-inflammatory agent(s) are selected from
selected from etodolac, famotidine, fenoprofen, fenoprofen, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol,
nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, apricoxib,
robenacoxib, valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib, rofecoxib,
mavacoxib, and firocoxib. For instance, in some embodiments, the methods for the treatment,
prevention, and/or amelioration of edema, e.g., lymphedema comprise administering
to a subject in need thereof a deuterium-enriched pirfenidone, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including , for example,e.g., a
compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
one or more anti-TGF-β1 agent(s), e.g., a deuterium enricher pirfendone described
herein other than LYT-100, and ibuprofen.
[0407] Provided herein are methods for treatment, prevention, and/or amelioration of one
or more symptoms of edema, e.g., lymphedema comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100, in combination
with one or more anti-TGF-β1 agent(s) and optionally one or more anti-inflammatory
agent(s). In some embodiments, the methods for treatment, prevention, and/or amelioration
of one or more symptoms of edema, e.g., lymphedema comprise administering to a subject
in need thereof a deuterium-enriched pirfenidone, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one or more anti-TGF-β1
agent(s) selected from LY550410, LY580276, SB-505124, (LY2157299 Monohydrate) , and
deuterium-enriched pirfenidone, e.g., as described herein, other than LYT-100, and
one or more anti-inflammatory agent(s). In some embodiments, the one or more anti-inflammatory
agent(s) are selected from selected from etodolac, famotidine, fenoprofen, fenoprofen,
flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic
acid, meloxicam, misoprostol, nabumetone, naproxen, oxaprozin, piroxicam, sulindac,
tolmetin, celecoxib, apricoxib, robenacoxib, valdecoxib, anitrazafen, tilmacoxib,
flumizole, cimicoxib, rofecoxib, mavacoxib, and firocoxib. For instance, in some embodiments,
the methods for treatment, prevention, and/or amelioration of one or more symptoms
of edema, e.g., lymphedema comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including, for example,e.g., a compound of Formula I, e.g., a compound listed in
Table 1, including e.g., LYT-100, one or more anti-TGF-β1 agent(s), e.g., a deuterium
enricher pirfendone described herein other than LYT-100, and ibuprofen.
[0408] Provided herein are methods for treatment, prevention, and/or amelioration of IPF
and/or one or more symptoms of IPF comprising administering to a subject in need thereof
a deuterium-enriched pirfenidone compound, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including, e.g., LYT-100, in combination with one or
more anti-TGF-β1 agent(s) and optionally one or more anti-inflammatory agent(s). In
some embodiments, the methods for treatment, prevention, and/or amelioration of IPF
and/or one or more symptoms of IPF comprise administering to a subject in need thereof
a deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g., a compound
listed in Table 1, including e.g., LYT-100, and one or more anti-TGF-β1 agent(s) selected
from LY550410, LY580276, SB-505124, (LY2157299 Monohydrate) , and deuterium-enriched
pirfenidone, e.g., as described herein, other than LYT-100, and one or more anti-inflammatory
agent(s). In some embodiments, the one or more anti-inflammatory agent(s) are selected
from selected from etodolac, famotidine, fenoprofen, fenoprofen, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol,
nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, apricoxib,
robenacoxib, valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib, rofecoxib,
mavacoxib, and firocoxib. For instance, in some embodiments, the methods for treatment,
prevention, and/or amelioration of IPF and/or one or more symptoms of IPF comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including , for example,e.g.,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
one or more anti-TGF-β1 agent(s), e.g., a deuterium enricher pirfendone described
herein other than LYT-100, and ibuprofen.
[0409] Provided herein are methods for the treatment, prevention, and/or amelioration of
a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering
to a subject in need thereof a deuterium-enriched pirfenidone compound, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100,
in combination with one or more anti-T cell agent(s) and optionally an anti-angiotensin
agent. In some embodiments, the methods for the treatment, prevention, and/or amelioration
of a fibrotic-mediated disorder and/or a collagen-mediated disorder comprise administering
to a subject in need thereof a deuterium-enriched pirfenidone, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one
or more anti-T cell agent(s) selected from tacrolimus, teriflunomide, leflunomide,
cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab. In some embodiments,
the anti-angiotensin agent is selected from captopril, zofenopril, enalapril, lisinopril,
ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril, cilazapril,
fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan,
fimasartan, diminazene aceturate, xanthenone, and AVE 099. For instance, in some embodiments,
the methods for the treatment, prevention, and/or amelioration of a fibrotic-mediated
disorder and/or a collagen-mediated disorder comprise administering to a subject in
need thereof a deuterium-enriched pirfenidone , for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, tacrolimus and optionally
captopril. In some embodiments, the methods for the treatment, prevention, and/or
amelioration of a fibrotic-mediated disorder and/or a collagen-mediated disorder comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
teriflunomide and optionally captopril.
[0410] Provided herein are methods for the treatment, prevention, and/or amelioration of
edema, e.g., lymphedema comprising administering to a subject in need thereof a deuterium-enriched
pirfenidone compound, for example, a compound of Formula I, e.g., a compound listed
in Table 1, including, e.g., LYT-100, in combination with one or more anti-T cell
agent(s) and optionally an anti-angiotensin agent. In some embodiments, the methods
for the treatment, prevention, and/or amelioration of edema, e.g., lymphedema comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
and one or more anti-T cell agent(s) selected from tacrolimus, teriflunomide, leflunomide,
cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab. In some embodiments,
the anti-angiotensin agent is selected from captopril, zofenopril, enalapril, lisinopril,
ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril, cilazapril,
fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan,
fimasartan, diminazene aceturate, xanthenone, and AVE 099. For instance, in some embodiments,
the methods for the treatment, prevention, and/or amelioration of edema, e.g., lymphedema
comprise administering to a subject in need thereof a deuterium-enriched pirfenidone
, for example, a compound of Formula I, e.g., a compound listed in Table 1, including
e.g., LYT-100, tacrolimus and optionally captopril. In some embodiments, the methods
for the treatment, prevention, and/or amelioration of edema, e.g., lymphedema comprise
administering to a subject in need thereof a deuterium-enriched pirfenidone, for example,
a compound of Formula I, e.g., a compound listed in Table 1, including e.g., LYT-100,
teriflunomide and optionally captopril.
[0411] Provided herein are methods for treatment, prevention, and/or amelioration of one
or more symptoms of edema, e.g., lymphedema comprising administering to a subject
in need thereof a deuterium-enriched pirfenidone compound, for example, a compound
of Formula I, e.g., a compound listed in Table 1, including, e.g., LYT-100, in combination
with one or more anti-T cell agent(s) and optionally an anti-angiotensin agent. In
some embodiments, the methods for treatment, prevention, and/or amelioration of one
or more symptoms of edema, e.g., lymphedema comprise administering to a subject in
need thereof a deuterium-enriched pirfenidone, for example, a compound of Formula
I, e.g., a compound listed in Table 1, including e.g., LYT-100, and one or more anti-T
cell agent(s) selected from tacrolimus, teriflunomide, leflunomide, cyclosporine,
pimecrolimus, denileukin diftitox, and basiliximab. In some embodiments, the anti-angiotensin
agent is selected from captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril,
perindopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan,
irbesartan, olmesartan, candesartan, telmisartan, valsartan, fimasartan, diminazene
aceturate, xanthenone, and AVE 099. For instance, in some embodiments, the methods
for treatment, prevention, and/or amelioration of one or more symptoms of edema, e.g.,
lymphedema comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone , for example, a compound of Formula I, e.g., a compound listed in Table
1, including e.g., LYT-100, tacrolimus and optionally captopril. In some embodiments,
the methods for treatment, prevention, and/or amelioration of one or more symptoms
of edema, e.g., lymphedema comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including e.g., LYT-100, teriflunomide and optionally captopril.
[0412] Provided herein are methods for treatment, prevention, and/or amelioration of IPF
and/or one or more symptoms of IPF comprising administering to a subject in need thereof
a deuterium-enriched pirfenidone compound, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including, e.g., LYT-100, in combination with one or
more anti-T cell agent(s) and optionally an anti-angiotensin agent. In some embodiments,
the methods for treatment, prevention, and/or amelioration of IPF and/or one or more
symptoms of IPF comprise administering to a subject in need thereof a deuterium-enriched
pirfenidone, for example, a compound of Formula I, e.g., a compound listed in Table
1, including e.g., LYT-100, and one or more anti-T cell agent(s) selected from tacrolimus,
teriflunomide, leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab.
In some embodiments, the anti-angiotensin agent is selected from captopril, zofenopril,
enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril,
cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan,
valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE 099. For instance,
in some embodiments, the methods for treatment, prevention, and/or amelioration of
IPF and/or one or more symptoms of IPF comprise administering to a subject in need
thereof a deuterium-enriched pirfenidone , for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, tacrolimus and optionally captopril.
In some embodiments, the methods for treatment, prevention, and/or amelioration of
IPF and/or one or more symptoms of IPF comprise administering to a subject in need
thereof a deuterium-enriched pirfenidone, for example, a compound of Formula I, e.g.,
a compound listed in Table 1, including e.g., LYT-100, teriflunomide and optionally
captopril.
Pharmaceutical Compositions, Formulations, Dosage Forms, and Administration
[0413] According to another embodiment, the present invention provides a composition comprising
a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable excipient, carrier, adjuvant, diluent, or vehicle. The amount of compound
in the composition is an amount effective to treat the relevant disease, disorder,
or condition in a patient in need thereof (an "effective amount"). For example, in
some embodiments, the "effective amount" of deuterium-enriched pirfenidone is a dosage
of deuterium-enriched pirfenidone, e.g., LYT-100, provided herein for the treatment,
prevention, and/or amelioration of one or symptoms of a fibrotic-mediated disorder
and/or a collagen-mediated disorder, such as any of the fibrotic-mediated disorders
and/or a collagen-mediated disorders disclosed herein, including, for example, edema
and lymphedema. In some embodiments, a composition of the present disclosure is formulated
for oral administration to a patient.
[0414] The term "pharmaceutically acceptable excipient, carrier, adjuvant, diluent, or vehicle"
refers to a non-toxic excipient, carrier, adjuvant, diluent, or vehicle that does
not destroy the pharmacological activity of the agent with which it is formulated.
Pharmaceutically acceptable excipients, carriers, adjuvants, diluents, or vehicles
that may be used in the disclosed compositions include, but are not limited to, ion
exchangers, alumina, stearates such as aluminum stearate, lecithin, serum proteins
such as human serum albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids,
water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate,
potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,
sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block
polymers, polyethylene glycol and wool fat. In some embodiments, the composition is
formulated as a lipophilic mixture, such as a lipid-based composition.
[0415] Compositions of the present invention may be administered orally, parenterally, enterally,
intracisternally, intraperitoneally, by inhalation spray, topically, rectally, nasally,
buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein
includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection
or infusion techniques. In some embodiments, the composition is administered orally,
intraperitoneally, or intravenously. In some embodiments, the composition is a transmucosal
formulation. In some embodiments, the composition is injected directly into the lymphatic
system. Sterile injectable forms of the compositions of this invention may be aqueous
or oleaginous suspension. These suspensions may be formulated according to techniques
known in the art using suitable dispersing or wetting agents and suspending agents.
The sterile injectable preparation may also be a sterile injectable solution or suspension
in a non-toxic parenterally acceptable diluent or solvent, for example as a solution
in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed
are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile,
fixed oils are conventionally employed as a solvent or suspending medium.
[0416] To aid in delivery of the composition, any bland fixed oil may be employed including
synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride
derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable
oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
These oil solutions or suspensions may also contain a long-chain alcohol diluent or
dispersant, such as carboxymethyl cellulose or similar dispersing agents that are
commonly used in the formulation of pharmaceutically acceptable dosage forms including
emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are commonly used
in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms
may also be used for the purposes of formulation.
[0417] Pharmaceutically acceptable compositions may be orally administered in any orally
acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions
or solutions. In the case of tablets for oral use, carriers commonly used include
lactose and corn starch. Lubricating agents, such as magnesium stearate, may also
be added. For oral administration in a capsule form, useful diluents include lactose
and dried corn starch. When aqueous suspensions are required for oral use, the active
ingredient is combined with emulsifying and suspending agents. If desired, certain
sweetening, flavoring or coloring agents may also be added.
[0418] Alternatively, pharmaceutically acceptable compositions may be administered in the
form of suppositories for rectal administration. These can be prepared by mixing the
agent with a suitable non-irritating excipient that is solid at room temperature but
liquid at rectal temperature and therefore will melt in the rectum to release the
drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[0419] In some embodiments, the pharmaceutically acceptable composition is formulated for
oral administration. Such formulations may be administered with or without food. In
some embodiments, the pharmaceutically acceptable composition is administered without
food. In other embodiments, the pharmaceutically acceptable composition is administered
with food.
[0420] It should also be understood that a specific dosage and treatment regimen for any
particular patient will depend upon a variety of factors, including the activity of
the specific compound employed, the age, body weight, general health, sex, diet, time
of administration, rate of excretion, drug combination, and the judgment of the treating
physician and the severity of the particular disease being treated.
[0421] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically
acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
In addition to the active compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other solvents, solubilizing
agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,
ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive,
castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols
and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the
oral compositions can also include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0422] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions
may be formulated according to the known art using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation may also be a sterile
injectable solution, suspension or emulsion in a nontoxic parenterally acceptable
diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and
isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose any bland fixed oil can
be employed including synthetic mono- or diglycerides. In addition, fatty acids such
as oleic acid are used in the preparation of inj ectables.
[0423] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining
filter, or by incorporating sterilizing agents in the form of sterile solid compositions
which can be dissolved or dispersed in sterile water or other sterile injectable medium
prior to use.
[0424] In order to prolong the effect of a compound of the present invention, it is often
desirable to slow the absorption of the compound from subcutaneous or intramuscular
injection. This may be accomplished by the use of a liquid suspension of crystalline
or amorphous material with poor water solubility. The rate of absorption of the compound
then depends upon its rate of dissolution that, in turn, may depend upon crystal size
and crystalline form. Alternatively, delayed absorption of a parenterally administered
compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the compound
in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio
of compound to polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other biodegradable polymers include
poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are compatible with
body tissues.
[0425] Compositions for rectal or vaginal administration are preferably suppositories which
can be prepared by mixing the compounds of this invention with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or a suppository
wax which are solid at ambient temperature but liquid at body temperature and therefore
melt in the rectum or vaginal cavity and release the active compound.
[0426] Solid dosage forms for oral administration include capsules, tablets, pills, powders,
and granules. In such solid dosage forms, the active compound is mixed with at least
one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate
or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose,
glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such
as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution
retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate,
h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium
stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and
mixtures thereof. In the case of capsules, tablets and pills, the dosage form may
also comprise buffering agents.
[0427] Solid compositions of a similar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or milk sugar as well
as high molecular weight polyethylene glycols and the like. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared with coatings and
shells such as enteric coatings and other coatings well known in the pharmaceutical
formulating art. They may optionally contain opacifying agents and can also be of
a composition that they release the active ingredient(s) only, or preferentially,
in a certain part of the intestinal tract, optionally, in a delayed manner. Examples
of embedding compositions that can be used include polymeric substances and waxes.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as well as high molecular
weight polethylene glycols and the like.
[0428] Therapeutic agents can also be in micro-encapsulated form with one or more excipients
as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules
can be prepared with coatings and shells such as enteric coatings, release controlling
coatings and other coatings well known in the pharmaceutical formulating art. In such
solid dosage forms the active compound may be admixed with at least one inert diluent
such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal
practice, additional substances other than inert diluents, e.g., tableting lubricants
and other tableting aids such a magnesium stearate and microcrystalline cellulose.
In the case of capsules, tablets and pills, the dosage forms may also comprise buffering
agents. They may optionally contain opacifying agents and can also be of a composition
that they release the active ingredient(s) only, or preferentially, in a certain part
of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes.
[0429] Dosage forms for topical or transdermal administration of a compound of this invention
include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants
or patches. The active component is admixed under sterile conditions with a pharmaceutically
acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic
formulation, ear drops, and eye drops are also contemplated as being within the scope
of this invention. Additionally, the present invention contemplates the use of transdermal
patches, which have the added advantage of providing controlled delivery of a compound
to the body. Such dosage forms can be made by dissolving or dispensing the compound
in the proper medium. Absorption enhancers can also be used to increase the flux of
the compound across the skin. The rate can be controlled by either providing a rate
controlling membrane or by dispersing the compound in a polymer matrix or gel.
[0430] In some embodiments, the compound is formulated as an orally administerable, lipid-based
formulation. Lipid-based formulations for oral delivery are known in the art and may
include, for example, substantially non-aqueous vehicles which typically contain one
or more lipid components. The lipid vehicles and resulting lipid formulations may
be usefully classified as described below according to their shared common features
according to the lipid formulation classification system (LFCS) (
Pouton, C. W., Eur. J. Pharm. Sci. 11 (Supp 2), S93-S98, 2000;
Pouton, C. W., Eur. J. Pharm. Sci. 29 278-287, 2006).
[0431] Lipid vehicles, and the resulting lipid formulations, may contain oil/lipids and/or
surfactants, optionally with co-solvents. In the LFCS terminology, Type I formulations
include oils or lipids which require digestion, such as mono, di and tri-glycerides
and combinations thereof. Type II formulations are water-insoluble self emulsifying
drug delivery systems (SEDDS) which contain lipids and oils used in Type I formulations,
with additional water insoluble surfactants. Type III formulations are SEDDS or self-microemulsifying
drug delivery systems (SMEDDS) which contain lipids and oils used in Type I formulations,
with additional water-soluble surfactants and/or co-solvents (Type IIIa) or a greater
proportion of water-soluble components (Type IIIb). Type IV formulations contain predominantly
hydrophilic surfactants and co-solvents (e.g. PEG, propylene glycol and diethylene
glycol monoethyl ether) and are useful for drugs which are poorly water soluble but
not lipophilic. Any such lipid formulation (Type I-IV) is contemplated herein for
use with a disclosed compound or pharmaceutical composition thereof.
[0432] In some embodiments, the lipid vehicle contains one or more oils or lipids, without
additional surfactants, co-surfactants or co-emulsifiers, or co-solvents, i.e. it
consists essentially of one or more oils or lipids. In some further embodiments, the
lipid vehicle contains one or more oils or lipids together with one or more water-insoluble
surfactants, optionally together with one or more co-solvents. In some embodiments,
the lipid vehicle contains one or more oils or lipids together with one or more water-soluble
surfactants, optionally together with one or more co-solvents. In some embodiments,
the lipid vehicle contains a mixture of oil/lipid, surfactant and co-solvent. In some
embodiments, the lipid vehicle consists essentially of one or more surfactants/co-surfactants/co-emulsifiers,
and/or solvents/co-solvents.
[0433] Examples of oils or lipids which may be used in the present invention include almond
oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut
oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape
seed oil, mustard seed oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed
oil, safflower oil, sesame oil, shark liver oil, soybean oil, sunflower oil, walnut
oil, wheat germ oil, avocado oil, bran oil, hydrogenated castor oil, hydrogenated
coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean
oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, caprylic/capric
glycerides, fractionated triglycerides, glyceryl tricaprate, glyceryl tricaproate,
glyceryl tricaprylate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate,
glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl
tricaprylate/caprate/stearate, glyceryl trilaurate, glyceryl monolaurate, glyceryl
behenate, glyceryl monolinoleate, glyceryl trilinolenate, glyceryl trioleate, glyceryl
triundecanoate, glyceryl tristearate linoleic glycerides, saturated polyglycolized
glycerides, synthetic medium chain triglycerides containing primarily C
8-12 fatty acid chains, medium chain triglycerides containing primarily C
8-12 fatty acid chains, long chain triglycerides containing primarily >C
12 fatty acid chains, modified triglycerides, fractionated triglycerides, and mixtures
thereof.
[0434] Examples of mono and diglycerides which may be used in such formulations include
glycerol mono- and diesters having fatty acid chains from 8 to 40 carbon atoms, including
hydrolysed coconut oils (e.g. Capmul
® MCM), hydrolysed corn oil (e.g. Maisine
™35-l). In some embodiments, the monoglycerides and diglycerides are mono-or di- saturated
fatty acid esters of glycerol having fatty acid chains of 8 to 18 carbon chain length
(e.g. glyceryl monostearate, glyceryl distearate, glyceryl monocaprylate, glyceryl
dicaprylate, glyceryl monocaprate and glyceryl dicaprate). Mixtures of fatty acids
("structured glycerides") adapted for enhancing the absorption and transport of lipid
soluble compounds are disclosed in, e.g.,
U.S. Patent No. 6,013,665, which is hereby incorporated by reference.
[0435] In some embodiments, a disclosed compound is formulated with an exosome, e.g., encapsulated
in an exosome. In some embodiments, the exosome is derived from milk of a mammal (milk
exosome). In some embodiments, a deuterium-enriched pirfenidone is formulated with
an exosome, e.g., encapsulated in an exosome. In some embodiments, deuterium-enriched
pirfenidone is formulated with a milk exosome. In some embodiments, a LYT-100is formulated
with an exosome, e.g., encapsulated in an exosome. In some embodiments, LYT-100is
formulated with a milk exosome.
[0437] Suitable surfactants for use in the lipid formulations include propylene glycol mono-
and di-esters of C
8-22 fatty acids, such as, but not limited to, propylene glycol monocaprylate, propylene
glycol dicaprylate, propylene glycol monolaurate, sold under trade names such as Capryol
® 90, Labrafac
® PG, Lauroglycol
® FCC, sugar fatty acid esters, such as, but not limited to, sucrose palmitate, sucrose
laurate, and sucrose stearate; sorbitan fatty acid esters such as, but not limited
to, sorbitan laurate, sorbitan palmitate, and sorbitan oleate; polyoxyethylene sorbitan
fatty acid esters such as, but not limited to, polysorbate 20, polysorbate 40, polysorbate
60, polysorbate 80, and polysorbate 85; polyoxyethylene mono- and di-fatty acid esters
including, but not limited to, polyoxyl 40 stearate and polyoxyl 40 oleate; a mixture
of polyoxyethylene mono- and di-esters of C
8-22 fatty acids and glyceryl mono-, di-, and tri-esters of C
8-22 fatty acids as sold under tradenames such as Labrasol
®, Gelucire
® 44/14, Gelucire
® 50/13, and Labrafil
®; polyoxyethylene castor oils compound such as, but not limited to, polyoxyl 35 castor
oil, polyoxyl 40 hydrogenated castor oil, and polyoxyl 60 hydrogenated castor oil,
as are sold under tradenames such as Cremophor
®/Kolliphor EL, Cremophor
®/Kolliphor
® RH40, and Cremophor
®/Kolliphor
® RH60; polyoxyethylene alkyl ethers including, but not limited to, polyoxyl 20 cetostearyl
ether and polyoxyl 10 oleyl ether; DL-α-tocopheryl polyethylene glycol succinate;
glyceryl mono-, di-, and tri-esters; glyceryl mono-, di-, and tri-esters of C
8-22 fatty acids; sucrose mono-, di-, and tri-esters; sodium dioctylsulfosuccinate; polyoxyethylene-polyoxypropylene
copolymers such as, but not limited to poloxamer 124, poloxamer 188, and poloxamer
407; polyoxyethylene ethers of C
8-22 fatty alcohols including, but not limited to, polyoxyethylenelauryl alcohol, polyoxyethylenecetyl
alcohol, polyoxyethylene stearyl alcohol, polyoxyethyleneoleyl alcohol, as sold under
tradenames such as Brij
® 35, Brij
® 58, Brij
® 78, Brij
® 98, or a mixture of any two or more thereof.
[0438] A co-emulsifier, or co-surfactant, may be used in the formulation. A suitable co-emulsifier
or co-surfactant may be a phosphoglyceride; a phospholipid, for example lecithin,
or a free fatty acid that is liquid at room temperature, for example, iso-stearic
acid, oleic acid, linoelic acid, linolenic acid, palmitic acid, stearic acid, lauric
acid, capric acid, caprylic acid, and caproic acid.
[0439] Suitable solvents/co-solvents include ethanol, propylene glycol, polyethylene glycol,
diethylene glycol monoethyl ether, and glycerol.
[0440] A polymer may also be used in the formulation to inhibit drug precipitation or to
alter the rate of drug release. A range of polymers have been shown to impart these
properties and are well known to those skilled in the art. Suitable polymers include
hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetyl succinate, other
cellulose-derived polymers such as methylcellulose; poly(meth)acrylates, such as the
Eudragit series of polymers, including Eudragit E100, polyvinylpyrrolidone, or others
as described in, e.g.
Warren et al., Mol. Pharmaceutics 2013, 10, 2823-2848.
[0441] Formulations may be chosen specifically to provide for sustained release of the active
in the gastrointestinal (GI) tract in order to control the rate of absorption. Many
different approaches may be used to achieve these ends including the use of high melting
point lipids that disperse/erode slowly in the GI tract, or polymers that form a matrix
that slowly erodes. These formulations may take the form of large monolithic dose
forms or may be present as micro or nano-particulate matrices as described in, for
example, in
Mishra, Handbook of Encapsulation and Controlled Release, CRC Press, Boca Raton, (2016)
ISBN 978-1-4822-3234-9,
Wilson and Crowley, Controlled Release in Oral Drug Delivery, Springer, NY, ISBN 978-1-4614-1004-1
(2011) or
Wise, Handbook of Pharmaceutical Controlled Release Technology, Marcel Dekker, NY,
ISBN 0-82467-0369-3 (2000).
[0442] Formulations may also contain materials commonly known to those skilled in the art
to be included in lipid based formulations, including antioxidants, for example, butylated
hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) and solidifying agents such
as microporous silica, for example magnesium alumino-metasilicate (Neusilin).
Combination Therapies
[0443] A disclosed compound or a pharmaceutically acceptable salt thereof, or pharmaceutical
composition thereof, may be administered to a patient in need thereof in combination
with one or more additional therapeutic agents and/or therapeutic processes.
[0444] The compound or a pharmaceutically acceptable salt or pharmaceutical composition
thereof can be administered alone or in combination with one or more other therapeutic
compounds, possible combination therapy taking the form of fixed combinations or the
administration of the compound or composition and one or more other therapeutic compounds
being staggered or given independently of one another, or the combined administration
of fixed combinations and one or more other therapeutic compounds. A compound or a
pharmaceutically acceptable salt or pharmaceutical composition thereof can besides
or in addition be administered for tumor therapy in combination with chemotherapy,
radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination
of these. Long-term therapy is equally possible as is adjuvant therapy in the context
of other treatment strategies, as described above. Other possible treatments are therapy
to maintain the patient's status after tumor regression, or even chemopreventive therapy,
for example in patients at risk.
[0445] Such additional agents may be administered separately from a compound or a pharmaceutically
acceptable salt or pharmaceutical composition thereof, as part of a multiple dosage
regimen. Alternatively, those agents may be part of a single dosage form, mixed together
with a disclosed compound in a single composition. If administered as part of a multiple
dosage regime, the two active agents may be submitted simultaneously, sequentially
or within a period of time from one another.
[0446] As used herein, the term "combination," "combined," and related terms refers to the
simultaneous or sequential administration of therapeutic agents in accordance with
the present disclosure. For example, a compound or a pharmaceutically acceptable salt
or pharmaceutical composition thereof may be administered with another therapeutic
agent simultaneously or sequentially in separate unit dosage forms or together in
a single unit dosage form. Accordingly, the present disclosure provides a single unit
dosage form comprising a disclosed compound, an additional therapeutic agent, and
a pharmaceutically acceptable excipient, carrier, adjuvant, diluent, or vehicle. In
some embodiments, the additional agent is formulated in a separate composition from
the disclosed compound.
[0447] The amount of both a disclosed compound or a pharmaceutically acceptable salt or
pharmaceutical composition thereof and additional therapeutic agent (in those compositions
which comprise an additional therapeutic agent as described above) that may be combined
with the carrier materials to produce a single dosage form will vary depending upon
the patient treated and the particular mode of administration. In certain embodiments,
compositions of this invention are formulated so that a dosage of between 0.01-100
mg/kg body weight/day of a disclosed compound can be administered.
[0448] In those compositions which comprise an additional therapeutic agent, that additional
therapeutic agent and the disclosed compound may act synergistically. Therefore, the
amount of additional therapeutic agent in such compositions will be less than that
required in a monotherapy utilizing only that therapeutic agent. In such compositions,
a dosage of between 0.01-100 mg/kg body weight/day of the additional therapeutic agent
can be administered.
[0449] The amount of additional therapeutic agent present in the compositions of this invention
will be no more than the amount that would normally be administered in a composition
comprising that therapeutic agent as the only active agent. In some embodiments, the
amount of additional therapeutic agent in the presently disclosed compositions will
range from about 50% to 100% of the amount normally present in a composition comprising
that agent as the only therapeutically active agent.
[0450] The structure of the active compounds identified by code numbers, generic or trade
names may be taken from the actual edition of the standard compendium "The Merck Index"
or from databases, e.g. Patents International (e.g. IMS World Publications).
[0451] The exact amount of therapeutic agent required to be effective in any treatment regimen
will vary from subject to subject, depending on the species, age, and general condition
of the subject, the severity of the infection, the particular agent, its mode of administration,
and the like. Disclosed compounds are preferably formulated in unit dosage form for
ease of administration and uniformity of dosage. The expression "unit dosage form"
as used herein refers to a physically discrete unit of agent appropriate for the patient
to be treated. It will be understood, however, that the total daily usage of a disclosed
compound or a pharmaceutically acceptable salt or pharmaceutical composition thereof
and any co-administered additional therapeutic agents will be decided by the attending
physician within the scope of sound medical judgment. The specific effective dose
level for any particular patient or organism will depend upon a variety of factors
including the disorder being treated and the severity of the disorder; the activity
of the specific compound employed; the specific composition employed; the age, body
weight, general health, sex and diet of the patient; the time of administration, route
of administration, and rate of excretion of the specific compound or composition;
the duration of the treatment; drugs used in combination or coincidental with the
specific compound or composition employed, and like factors well known in the medical
arts.
[0452] The term "subject" or "patient," as used herein, means any subject, such as an animal,
for example a mammalian subject, for whom diagnosis, prognosis, or therapy is desired.
Mammalian subjects include humans, domestic animals, farm animals, sports animals,
and zoo animals including, e.g., humans, non-human primates, dogs, cats, guinea pigs,
rabbits, rats, mice, horses, cattle, and so on. In some embodiments, the term "subject"
is meant to include a "patient". In some embodiments, the term "patient" is meant
to refer to a mammalian subject, including a human subject. In some embodiments, the
patient is human subject.
[0453] In some embodiments, pirfenidone or deuterium-enriched pirfenidone is co-administered
with one or more additional therapeutic agents selected from sepsis agents, antibacterials,
anti-fungals, anti-coagulants, thrombolytics, steroidal drugs, non-steroidal anti-inflammatory
drugs (NSAIDs), opioids, anesthetics, calcium channel blockers, Beta-blockers, nitrates
or nitrites, ACE inhibitors, statins, platelet aggregation inhibitors, adenosine,
digitoxin, anti-arrhythmic agents, sympathomimetic drugs, endothelin converting enzyme
(ECE) inhibitors, thromboxane enzyme antagonists, potassium channel openers, thrombin
inhibitors, growth factor inhibitors, platelet activating factor (PAF) antagonists,
anti-platelet agents, Factor VIIa Inhibitors, Factor Xa Inhibitors, renin inhibitors,
neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors, HMG CoA reductase
inhibitors, squalene synthetase inhibitors, fibrates, bile acid sequestrants, anti-atherosclerotic
agents, MTP Inhibitors, potassium channel activators, alpha-PDE5 agents, beta-PDE5
agents, diuretics, anti-diabetic agents, PPAR-gamma agonists, mineralocorticoid enzyme
antagonists, aP2 inhibitors, protein tyrosine kinase inhibitors, antiinflammatories,
antiproliferatives, chemotherapeutic agents, immunosuppressants, anticancer agents,
cytotoxic agents, antimetabolites, farnesyl-protein transferase inhibitors, hormonal
agents, microtubule-disruptor agents, microtubule-stablizing agents, topoisomerase
inhibitors, prenyl-protein transferase inhibitors, cyclosporins, TNF-alpha inhibitors,
cyclooxygenase-2 (COX-2) inhibitors, gold compounds, antalarmin, Z-338 and platinum
coordination complexes.
[0454] In some embodiments, the additional therapeutic agent is a steroidal drug.
[0455] In some embodiments, the steroidal drug is selected from the group consisting of
aldosterone, beclometasone, betamethasone, deoxycorticosterone acetate, fludrocortisone
acetate, hydrocortisone (cortisol), prednisolone, prednisone, methylprenisolone, dexamethasone,
and triamcinolone.
[0456] In some embodiments, said therapeutic agent is a non-steroidal anti-inflammatory
agent.
[0457] In some embodiments, the non-steroidal anti-inflammatory agent is selected from the
group consisting of aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorilate,
bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal,
etodolac, etoracoxib, faislamine, fenbuten, fenoprofen, flurbiprofen, ibuprofen, indometacin,
ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic
acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone,
naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl
salicylate, sulindac, sulfinprazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin.
[0458] In some embodiments, the compounds provided herein are combined with one or more
therapeutic agents for sepsis treatment, including, but not limited to, drotrecogin-α
or a biosimilar equivalent of activated protein C.
[0459] In certain embodiments, the compounds provided herein can be combined with one or
more steroidal drugs, including, but not limited to, aldosterone, beclometasone, betamethasone,
deoxycorticosterone acetate, fludrocortisone acetate, hydrocortisone (cortisol), prednisolone,
prednisone, methylprenisolone, dexamethasone, and triamcinolone.
[0460] In other embodiments, the compounds provided herein can be combined with one or more
antibacterial agents, including, but not limited to, amikacin, amoxicillin, ampicillin,
arsphenamine, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor,
cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime,
cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten,
ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin,
clindamycin, cloxacillin, colistin, dalfopristan, demeclocycline, dicloxacillin, dirithromycin,
doxycycline, erythromycin, enafloxacin, ertepenem, ethambutol, flucloxacillin, fosfomycin,
furazolidone, gatifloxacin, geldanamycin, gentamicin, herbimicin, imipenem, isoniazide,
kanamicin, levofloxacin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin,
meropenem, metronidazole, mezlocillin, minocycline, mupirozin, nafcillin, neomycin,
netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oxytetracycline, penicillin, piperacillin,
platensimycin, polymixin B, prontocil, pyrazinamide, quinupristine, rifampin, roxithromycin,
spectinomycin, streptomycin, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin,
telithromycin, tetracycline, ticarcillin, tobramycin, trimethoprim, troleandomycin,
trovafloxacin, and vancomycin.
[0461] In some embodiments, the compounds provided herein can be combined with one or more
antifungal agents, including, but not limited to, amorolfine, amphotericin B, anidulafungin,
bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole,
fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin,
miconazole, naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole,
rimocidin, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, and
voriconazole.
[0462] In other embodiments, the compounds provided herein can be combined with one or more
anticoagulants, including, but not limited to, acenocoumarol, argatroban, bivalirudin,
lepirudin, fondaparinux, heparin, phenindione, warfarin, and ximalagatran.
[0463] In certain embodiments, the compounds provided herein can be combined with one or
more thrombolytics, but not limited to, anistreplase, reteplase, t-PA (alteplase activase),
streptokinase, tenecteplase, and urokinase.
[0464] In certain embodiments, the compounds provided herein can be combined with one or
more non-steroidal anti-inflammatory agents, including, but not limited to, aceclofenac,
acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib,
choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoracoxib, faislamine,
fenbuten, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac,
lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam,
metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide,
oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac,
sulfinprazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin.
[0465] In some embodiments, the compounds provided herein can be combined with one or more
antiplatelet agents, including, but not limited to, abciximab, cilostazol, clopidogrel,
dipyridamole, ticlopidine, and tirofibin.
[0466] The compounds disclosed herein can also be administered in combination with other
classes of compounds, including, but not limited to, anti-arrhythmic agents, such
as propranolol; sympathomimetic drugs, such as norepinephrine; opioids, such as tramadol;
anesthetics, such as ketamine; calcium channel blockers, such as diltiazem; Beta-blockers,
such as atenolol; nitrates or nitrites, such as glyceryl trinitrate; endothelin converting
enzyme (ECE) inhibitors, such as phosphoramidon; thromboxane receptor antagonists,
such as ifetroban; potassium channel openers; thrombin inhibitors, such as hirudin;
growth factor inhibitors, such as modulators of PDGF activity; platelet activating
factor (PAF) antagonists; anti-platelet agents, such as GPIIb/IIIa blockers (e.g.,
abdximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine
and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins,
such as enoxaparin; Factor VIIa Inhibitors and Factor Xa Inhibitors; renin inhibitors;
neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors),
such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin,
lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or
nisbastatin), and ZD-4522 (also known as rosuvastatin, or atavastatin or visastatin);
squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran;
niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium
channel blockers, such as amlodipine besylate; potassium channel activators; alpha-adrenergic
agents; diuretics, such as chlorothlazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,
bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothlazide,
ethacrynic acid, tricrynafen, chlorthalidone, furosenilde, musolimine, bumetanide,
triamterene, amiloride, and spironolactone; thrombolytic agents, such as tissue plasminogen
activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated
plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as
biguanides (e.g. metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides
(e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide),
thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma
agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone;
growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, such as
PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil,
vardenafil); protein tyrosine kinase inhibitors; antiinflammatories; antiproliferatives,
such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic
agents; immunosuppressants; anticancer agents and cytotoxic agents (e.g., alkylating
agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines,
and triazenes); antimetabolites, such as folate antagonists, purine analogues, and
pyrridine analogues; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin,
and plicamycin; enzymes, such as L-asparaginase; farnesyl-protein transferase inhibitors;
hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens,
androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone anatagonists,
and octreotide acetate; microtubule-disruptor agents, such as ecteinascidins; microtubule-stablizing
agents, such as pacitaxel, docetaxel, and epothilones A-F; plant-derived products,
such as vinca alkaloids, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors;
prenyl-protein transferase inhibitors; and cyclosporins; steroids, such as prednisone
and dexamethasone; cytotoxic drugs, such as azathiprine and cyclophosphamide; TNF-alpha
inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptor, such as
etanercept, rapamycin, and leflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such
as celecoxib and rofecoxib; and miscellaneous agents such as, hydroxyurea, procarbazine,
mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, such
as cisplatin, satraplatin, and carboplatin.
Kits/Articles of Manufacture
[0467] For use in the therapeutic applications described herein, kits and articles of manufacture
are also described herein. Such kits can comprise a carrier, package, or container
that is compartmentalized to receive one or more containers such as vials, tubes,
and the like, each of the container(s) comprising one of the separate elements to
be used in a method described herein. Suitable containers include, for example, bottles,
vials, syringes, and test tubes. The containers can be formed from a variety of materials
such as glass or plastic.
[0468] For example, the container(s) can comprise one or more compounds described herein,
optionally in a composition or in combination with another agent as disclosed herein.
The container(s) optionally have a sterile access port (for example the container
can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic
injection needle). Such kits optionally comprise a compound with an identifying description
or label or instructions relating to its use in the methods described herein.
[0469] A kit will typically comprise one or more additional containers, each with one or
more of various materials (such as reagents, optionally in concentrated form, and/or
devices) desirable from a commercial and user standpoint for use of a compound described
herein. Non-limiting examples of such materials include, but are not limited to, buffers,
diluents, filters, needles, syringes; carrier, package, container, vial and/or tube
labels listing contents and/or instructions for use, and package inserts with instructions
for use. A set of instructions will also typically be included.
[0470] A label can be on or associated with the container. A label can be on a container
when letters, numbers or other characters forming the label are attached, molded or
etched into the container itself; a label can be associated with a container when
it is present within a receptacle or carrier that also holds the container, e.g.,
as a package insert. A label can be used to indicate that the contents are to be used
for a specific therapeutic application. The label can also indicate directions for
use of the contents, such as in the methods described herein. These other therapeutic
agents may be used, for example, in the amounts indicated in the Physicians' Desk
Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
4. Methods of Making Deuterium-Enriched Compounds
General Methods for Making Deuterium-Enriched Compounds
[0471] The compounds of this invention may be prepared or isolated in general by synthetic
and/or semi-synthetic methods known to those skilled in the art for analogous compounds
and by methods described in detail herein. Synthesis of certain A-aryl pyridinones
of the present invention, including pirfenidone and deuterium-enriched pirfenidone
compounds, are described in
WO 2008/157786,
WO 2009/035598,
WO 2012/122165, and
WO 2015/112701, the entireties of which are hereby incorporated by reference.
[0472] In some embodiments, protecting groups (as defined below) can be used to manipulate
therapeutic agents in preparation of the final compound, for example, to prevent undesired
side reactions from taking place.
[0473] In the synthesis methods described herein, where a particular protecting group ("PG"),
leaving group ("LG"), or transformation condition is depicted, one of ordinary skill
in the art will appreciate that other protecting groups, leaving groups, and transformation
conditions are also suitable and are contemplated. Such groups and transformations
are described in detail in
March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith
and J. March, 7th Edition, John Wiley & Sons, 2013,
Comprehensive Organic Transformations, R. C. Larock, 3rd Edition, John Wiley & Sons,
2018, and
Protective Groups in Organic Synthesis, P. G. M. Wuts, 5th edition, John Wiley &
Sons, 2014, the entirety of each of which is hereby incorporated herein by reference.
[0474] As used herein, the phrase "leaving group" (LG) includes, but is not limited to,
halogens (
e.g., fluoride, chloride, bromide, iodide), sulfonates (
e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium,
and the like.
[0475] As used herein, the phrase "oxygen protecting group" includes, for example, carbonyl
protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are
well known in the art and include those described in detail in
Protective Groups in Organic Synthesis, P. G. M. Wuts, 5th edition, John Wiley & Sons,
2014, and
Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York,
1994, the entireties of which are incorporated herein by reference. Examples of suitable
hydroxyl protecting groups include, but are not limited to, esters, allyl ethers,
ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples
of such esters include formates, acetates, carbonates, and sulfonates. Specific examples
include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate,
triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate,
4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate,
benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl,
ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl,
allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl
ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,
trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers
include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl,
benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.
Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl,
O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and
2- and 4-picolyl.
[0476] Amino protecting groups are well known in the art and include those described in
detail in
Protective Groups in Organic Synthesis, P. G. M. Wuts, 5th edition, John Wiley & Sons,
2014, and
Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference. Suitable amino protecting
groups include, but are not limited to, aralkylamines, carbamates, cyclic imides,
allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl
(Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl
(Alloc), benzyloxocarbonyl (Cbz), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl
(Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl,
trifluoroacetyl, benzoyl, and the like.
[0477] One of skill in the art will appreciate that various functional groups present in
compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters,
amides, aldehydes, halogens and nitriles can be interconverted by techniques well
known in the art including, but not limited to reduction, oxidation, esterification,
hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial
hydration, and hydration. See, for example,
March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith
and J. March, 7th Edition, John Wiley & Sons, 2013,
Comprehensive Organic Transformations, R. C. Larock, 3rd Edition, John Wiley & Sons,
2018, the entirety of each of which is incorporated herein by reference.
[0478] Embodiments of the present disclosure can be further defined by reference to the
following non-limiting examples. It will be apparent to those skilled in the art that
many modifications, both to materials and methods, can be practiced without departing
from the scope of the present disclosure.
EXEMPLIFICATION
[0479] Example 1 illustrates the unexpected pharmacokinetic profile of deuterated pirfenidone
which provides a significantly reduced pill burden and efficacy at a significantly
lower dose, with a significant potential for reducing dose-related side effects and
for reduced interpatient variability as compared to pirfenidone. Example 2 provides
a dosing and food effect study for deuterated pirfenidone as well as its efficacy
in lymphedema. Examples 3, 4, 5, and 6 illustrate the anti-fibrotic and anti-inflammatory
efficacy of deuterated pirfenidone.
Example 1: LYT-100 Increases Systemic Exposure in Humans
[0480] LYT-100 was studied in a single dose, double-blinded, cross-over clinical trial of
24 healthy volunteers to assess safety and pharmacokinetics (PK). Following screening,
eligible healthy volunteer subjects were admitted to a single clinical study site
and were randomized to 1 of 2 treatment sequences. Subjects received a single 801
mg oral dose of either LYT-001 or pirfenidone in Period 1 and, following washout,
crossed over to receive the other treatment in period 2. In each period, a standardized
breakfast was provided to subjects prior to administration of study drug (to compare
the PK profiles in the clinically relevant fed state) and plasma samples were collected
over a 48-hour period after dosing for evaluation of PK. Dosing between the 2 periods
was separated by a minimum of 7 days. Subjects completed the study upon completion
of the 48-hour post-dose assessments following dosing period 2.
[0481] To avoid confounding the analysis of results with any influence of formulations,
both study drugs (LYT-100 and pirfenidone) were synthesized using the same manufacturing
process and were provided as unformulated powder in capsules: LYT-100 801 mg (267
mg capsules x 3); and pirfenidone 801 mg (267 mg capsules x 3).
[0482] All capsules were identical in size, shape, and external color. Both the LYT-100
and the pirfenidone used in this trial were provided in hard-shell gelatin capsules
containing 267 mg of either LYT-100 or pirfenidone powder with no excipients. The
order of the two treatments was assigned via a randomization schema in a 1:1 ratio
such that half of the subjects received LYT-100 first and the other half received
pirfenidone first.
[0483] The plasma concentrations of LYT-100, pirfenidone, and their respective associated
metabolites (e.g., 5-carboxy-pirfenidone, 5-hydroxymethyl-pirfenidone, and 4'-hydroxy-
pirfenidone) and sample collection times were used for calculation of the following
pharmacokinetic parameters for each subject and treatment:
Cmax |
maximum observed plasma concentration, obtained directly from the Plasma concentration
time profile. |
tmax |
time of the maximum observed plasma concentration, obtained by inspection. If the
maximum Plasma concentration occurs at more than one time point, the first is chosen. |
AUC0-t |
the area under the plasma concentration versus time curve, from time 0 to the last
quantifiable concentration, calculated by the linear trapezoidal method. |
λz |
apparent first order terminal elimination rate, obtained from the slope of the line,
fitted by linear least squares regression, through the terminal points of the log
(base e) concentration-time profiles. |
t1/2 |
the apparent first-order terminal elimination half-life, calculated by the equation
t½ = ln(2)/ λz. |
AUC(inf) |
the area under the Plasma concentration versus time curve from time 0 extrapolated
to infinity, by adding Ct/λz to AUC0-t, where Ct is the last quantifiable concentration. |
%AUCextra p |
the percentage of AUC(inf) obtained by extrapolation, calculated by Ct/λz expressed as a percentage of the total AUC(inf). |
CL/F |
Oral clearance, calculated as (Dose / AUC0→∞) |
Vz/F |
volume of distribution during the terminal phase after oral administration, calculated
as (CL/F / λz) |
[0484] FIG. 1A and Tables 4-6 summarize the pharmacokinetics over 24 hours of the active LYT-100
(deupirfenidone) and control pirfenidone (LYT-101), their partially active metabolites,
deuterated 5-hydroxymethyl-pirfenidone (LYT-110) and nondeuterated 5-hydroxymethyl-pirfenidone
(LYT-111), respectively; and common metabolite, nondeuterated 5-carboxy-pirfenidone
(LYT-105).
FIG. 1B is an individual's single dose pharmacokinetics of an 801mg dose of LYT-100 and 801
mg dose of pirfenidone over 48 hours showing LYT-100, pirfenidone and the metabolites
of each. The mean Cmax values in Table 4 are different when compared with the maximum
concentration observed in
FIG. 1A. FIG. 1A is a plot of the mean of the concentration values calculated at each (nominal) time
point, producing a mean concentration time curve. The mean Cmax values are computed
from each individual subjects Cmax value (which could occur at different Tmax times
for each individual), i.e., the mean Cmax value reported in the PK parameter table
is not the Cmax for a mean concentration-time curve.
[0485] FIG. 1C is a model of a 500 mg twice daily dose of LYT-100 (total daily dose of 1000 mg)
on day 7 based on the clinical trial pharmacokinetics.
FIG. 1D is a model of a 750 mg twice daily dose of LYT-100 (total daily dose of 1500 mg)
on day 7 based on the clinical trial pharmacokinetics.
FIG. 1E is a model of the first 7 days of the dosing of
FIG. 1D showing accumulation to steady state.
FIG. 1F is a model of a 750 mg once daily dose of LYT-100 (total daily dose of 750 mg) on
day 7 based on the clinical trial pharmacokinetics.
Table 4: Summary of Key Pharmacokinetic Parameters for LYT-100 and Pirfenidone
Pharmacokinetic Parameter |
Statistics |
Treatment = LYT-100 |
Treatment = Pirfenidone |
(n=24) |
Analyte = LYT-100 |
Analyte = pirfenidone |
Cmax (ng/mL) |
Mean (CV%) |
8835 (27%) |
7100 (25%) |
tmax (hr) |
Median, (Range) |
2.25 (1.00 - 4.00) |
2.50 (1.50 - 4.00) |
AUC0-t (hr*ng/mL) |
Mean (CV%) |
56639 (46%) |
41091 (42%) |
AUC(inf) (hr*ng/mL) |
Mean (CV%) |
57032 (46%) |
41316 (42%) |
%AUC extrap |
Mean (CV%) |
0.674 (56%) |
0.602 (54%) |
Kel (1/hr) |
Mean (CV%) |
0.274 (35%) |
0.300 (27%) |
t1/2 (hr) |
Mean (CV%) |
2.81 (31%) |
2.48 (29%) |
CL/P (L/hr) |
Mean (CV%) |
17.8 (53%) |
23.5 (48%) |
Vz/F( L) |
Mean (CV%) |
63.1 (31%) |
76.5 (31%) |
Table 5: Summary of Key Pharmacokinetic Parameters for Partially Active Metabolites:
deuterated 5-hydroxymethyl-pirfenidone (LYT-110) and nondeuterated 5-hydroxymethyl-pirfenidone
(LYT-111)
Pharmacokinetic Parameter |
Statistics |
Treatment = LYT-100 |
Treatment = Pirfenidone |
(n=24) |
Analyte = LYT-110 |
Analyte = LYT-111 |
Cmax (ng/mL) |
Mean (CV%) |
20.6 (30%) |
17.1 (36%) |
tmax (hr) |
Median, (Range) |
2.50 (1.00 - 4.00) |
2.50 (1.50 - 4.00) |
AUC0-t (hr*ng/mL) |
Mean (CV%) |
111 (32%) |
75.8 (42%) |
AUC(inf) (hr*ng/mL) |
Mean (CV%) |
124 (32%)a |
89.7 (41%) b |
%AUC extrap |
Mean (CV%) |
10.1 (35%)a |
10.3 (33%) b |
Kel (1/hr) |
Mean (CV%) |
0.294 (44%) a |
0.367 (29%) b |
t1/2 (hr) |
Mean (CV%) |
2.76 (38%)a |
2.04 (29%) b |
Table 6: Summary of Key Pharmacokinetic Parameters for 5-carboxy-pirfenidone (LYT-105).
Pharmacokinetic Parameter |
Statistics |
Treatment = LYT-100 |
Treatment = Pirfenidone |
(n=24) |
Analyte = LYT-105 |
Analyte = LYT-105 |
Cmax (ng/mL) |
Mean (CV%) |
3970 (32%) |
5241 (31%) |
tmax (hr) |
Median, (Range) |
2.50 (1.50 - 4.00) |
3.00 (1.50 - 4.00) |
AUC0-t (hr*ng/mL) |
Mean (CV%) |
23090 (19%) |
26932 (19%) |
AUC(inf) (hr*ng/mL) |
Mean (CV%) |
23350 (19%) |
27159 (19%) |
%AUC extrap |
Mean (CV%) |
1.13 (63%) |
0.843 (58%) |
Kel (1/hr) |
Mean (CV%) |
0.262 (33%) |
0.288 (24%) |
t1/2 (hr) |
Mean (CV%) |
2.91 (30%) |
2.55 (25%) |
[0486] It was observed that the systemic exposure of LYT-100 was about 35% greater than
for pirfenidone, and about 25% greater for Cmax, with no appreciable difference in
the apparent elimination half-life.
[0487] The increased systemic exposure to LYT-100 was accompanied by changes in the relative
abundance of downstream metabolites. Following LYT-100 and pirfenidone, the most abundant
measured circulating metabolite was 5-carboxy-pirfenidone (LYT-105). 5-carboxy-pirfenidone
was reduced after LYT-100 relative to pirfenidone by approximately 15% and 25% for
AUC and Cmax, respectively. As a percent of the parent analyte AUC
0-∞, 5-carboxy-pirfenidone represented 43.8% for LYT-100 as compared to 65.9% for pirfenidone
(Table 7). The remaining measured metabolites, 5-hydroxymethyl-pirfenidone (LYT-111)
and 4'-hydroxy-pirfenidone (LYT-104), were far less abundant, representing less than
2% of parent in terms of AUC. The formation of the metabolite 5-hydroxymethyl-pirfenidone
was approximately 50% greater in terms of overall systemic exposure (AUC) after administration
of LYT-100. Similarly, 4'-hydroxy-pirfenidone was detectable more frequently after
LYT-100 than after pirfenidone. Given the low plasma concentrations of these metabolites,
however, these changes contributed little to the overall pharmacokinetic profile of
LYT-100 relative to pirfenidone.
Table 7: Summary of Metabolite/Parent Ratio, Overall
Pharmacokinetic Parameter |
Statistic |
Metabolite/Parent Ratioa |
Pirfenidone (LYT-101) |
LYT-100 |
LYT-105/ LYT-101 |
LYT-111/ LYT-101 |
LYT-104/ LYT-101 |
LYT-105/ LYT-100 |
LYT-110/ LYT-100 |
LYT-103/ LYT-100 |
Cmax (ng/mL) |
N |
24 |
24 |
24 |
24 |
24 |
24 |
Mean |
68.1% |
0.2% |
0.0% |
43.3% |
0.2% |
0.1% |
Std Dev |
29.0% |
0.1% |
0.0% |
22.2% |
0.1% |
0.0% |
CV(%) |
42.6% |
37.5% |
94.5% |
51.2% |
39.1% |
28.0% |
Median |
57.5% |
0.2% |
0.0% |
33.5% |
0.2% |
0.1% |
Minimum |
36.7% |
0.1% |
0.0% |
22.5% |
0.1% |
0.1% |
Maximum |
128.6% |
0.4% |
0.1% |
103.3% |
0.4% |
0.2% |
AUC0-∞ (hr*ng/mL) |
N |
24 |
19 |
0 |
24 |
23 |
10 |
Mean |
65.9% |
0.2% |
- |
43.8% |
0.2% |
0.1% |
Std Dev |
28.1% |
0.1% |
- |
22.4% |
0.1% |
0.0% |
CV(%) |
42.7% |
35.8% |
- |
51.2% |
38.0% |
33.8% |
Median |
53.7% |
0.2% |
- |
32.3% |
0.2% |
0.1% |
Minimum |
35.4% |
0.1% |
- |
21.2% |
0.1% |
0.1% |
Maximum |
128.9% |
0.4% |
- |
101.9% |
0.4% |
0.2% |
a The analytes were pirfenidone (LYT-101), nondeuterated 5-hydroxymethyl-pirfenidone
(LYT-111), nondeuterated 5-carboxy-pirfenidone (LYT-105), nondeuterated 4'-hydroxy-pirfenidone
(LYT-104), LYT-100 (deupirfenidone), deuterated 5-hydroxymethyl-pirfenidone (LYT-110),
and deuterated 4'-hydroxy-pirfenidone (LYT-103).
AUC0-∞=area under the plasma concentration versus time curve from zero to infinity; Cmax=maximum
observed plasma concentration; CV=coefficient of variation; hr=hour; mL=milliliter;
MW=molecular weight; N=number; ng=nanogram.
Metabolite/Parent Ratio Formula = Parameter (Metabolite)/Parameter (Parent) * MW (Parent)/MW
(Metabolite)
Pharmacokinetic parameters determined using Phoenix WinNonlin v6.3 (Certara) |
[0488] On average, after administration of LYT-100, the 5-carboxypirfenidone metabolite
(LYT-105) represented 43.8% of the parent in comparison to 65.9% of the parent after
administration of pirfenidone. This difference in exposure was not associated with
a change in half-life, suggesting formation, and not clearance of this non-deuterated
metabolite is affected by the deuterium substitution in the parent molecule.
[0489] Administration in the fed state of a single 801 mg dose of LYT-100 resulted in overall
greater exposure (AUC, Cmax) than observed with administration of an 801 mg dose of
pirfenidone. No appreciable difference in the apparent elimination t
½ or time to Cmax was observed for the 2 compounds. The higher peak and overall exposure
of LYT-100 was associated with a lower systemic exposure of the 5-carboxy-pirfenidone,
suggesting the kinetic isotope effect at least partially protects against pre-systemic
conversion of pirfenidone into 5-carboxy-pirfenidone.
[0490] The deuterium kinetic isotope effect appears independent of phenotype when comparing
exposure between deuterated and non-deuterated pirfenidone. CYP1A2 has been reported
as the main metabolizing enzyme for pirfenidone and higher enzyme activity in the
hyperinduced CYP1A2 phenotype is associated with lower exposure of both deuterated
and non-deuterated forms of pirfenidone relative to normal expression levels.
[0491] Overall, single doses of LYT-100 and pirfenidone were well tolerated and have a comparable
safety profile. No clinically significant differences were observed between the 2
treatments in terms of type, severity, or frequency of treatment emergent adverse
events. The most common adverse event following either treatment was headache. Of
interest, although administration of the 801 mg dose of LYT-100 resulted in greater
drug exposure than with the same pirfenidone dose, the incidence of gastrointestinal
and nervous system adverse events was not increased with LYT-100 administration as
compared to pirfenidone. No significant changes in laboratory parameters, vital signs,
or ECGs were observed following either treatment.
Example 2: L YT-100 Dosing and Food Effect Study, and Efficacy in Lymphedema
[0492] A multiple dose and food effect study of LYT-100 in healthy volunteers, and testing
for efficacy in patients with breast cancer-related upper limb secondary lymphedema
is being conducted.
[0493] The overall double-blind, placebo-controlled study design for Part 1 and Part 2:
evaluates the safety and tolerability of multiple doses of immediate-release LYT-100
versus placebo; compares the pharmacokinetic profiles of multiple doses of immediate-release
LYT-100 versus placebo over 5-days; compares the pharmacokinetic profiles of a maximally
tolerated dose (MTD); and evaluates the maximally tolerated dose and regimen.
[0494] The overall open-label design for Part 3 evaluates the effect of the doses of LYT-100
in patients with secondary lymphedema post-axial node dissection over a 24-week treatment
period. To further assess the safety, tolerability and pharmacokinetic profile of
LYT-100 over a 6-month dosing period, and study biomarkers and endpoints of disease
and progression in mild to moderate lymphedema in breast cancer-related lymphedema
patients taking LYT-100 are evaluated.
[0495] In Part 1, LYT-100 is dosed twice per day for 5 days following a 10 hour fast. The
first dose is administered 30 minutes into a standardized breakfast, followed by a
standardized lunch 4 hours later. The second dose is given 10 hours following the
morning dose and 30 minutes into a standardized dinner. Up to three different doses
of Immediate Release (IR) LYT-100 capsules ranging from 250 mg twice per day (BID)
up to 750 mg BID are studied. The study will start at a medium dose, e.g., 500 mg
BID and adjust to either lower or higher doses, with no dose exceeding 750 mg BID.
[0496] In Part 2, the maximally tolerated dose achieved in Part 1 is repeated for one day
with LYT-100 administered following a fasted single morning dose and single evening
dose administered 10 hours post-morning dose and on an empty stomach in healthy volunteers.
[0497] In Part 3, LYT-100 is dosed using the dose determined in Part 1 and 2, and is taken
twice per day as instructed for 24-weeks. Part 3 patients are males and females having
had breast cancer surgery at least 3 months prior, and who have completed radiation
treatment due to breast cancer at least one month prior. They are without recurrent
cancer ≥ 6 months after the breast cancer surgery. Patients are those having pitting
edema and
at least one of the following: increase in relative limb volume of between 10-20% as measured
by the truncated cone method of circumferential tape measurement, or a bioimpedance
measure of > +6.5 L-Dex. Patients are also on standard of care compression or agree
to use compression ≥ 4 weeks prior to screening if relative limb volume > 10% or L-Dex
> 14.
Table 8: Cohorts and Number of Subjects per Treatment Arm |
Cohort |
PART 1 A (Healthy Volunteers) |
Placebo |
LYT-100 |
LYT-100 dose |
1 |
Multiple Dose (n=8) |
2 subjects |
6 subjects |
500 mg, BID with food |
2 |
Multiple Dose (n=8) |
2 subjects |
6 subjects |
≤ 750 mg, BID* with food |
3 |
Multiple Dose (n=8) |
2 subjects A |
6 subjects A |
≤ 750 mg, BID* with food |
|
|
|
|
|
Cohort |
PART 2 A (Healthy Volunteers) |
Placebo |
LYT-100 |
LYT-100 dose |
4 |
Food Effect Cohort 4 (n=8) |
2 subjects A (7-day washout minimum between Cohort 3 and 4) |
6 subjects A (7-day washout minimum between Cohort 3 and 4) |
≤ 750 mg, BID**on an empty stomach |
|
|
|
|
|
Cohort |
PART 3 A (Patients with Secondary Lymphedema) |
Placebo |
LYT-100 |
LYT-100 dose |
5 |
Patient Cohort (n=32) |
0 subjects (will use historical data as reference) |
32 subjects |
≤ 750 mg, BID** |
A Subjects in the last cohort achieving the maximally tolerated dose of the multiple
dose study (e.g., Cohort 3) will return following a 7-day washout minimum from Part
1 dosing with meals and will return for Part 2 dosing fasting or on an empty stomach
(Cohort 4).
* Adjustment of dosing after prior cohort will be to either a lower or higher dose(s),
with no dose exceeding 750 mg BID (e.g., 250 mg, BID or 750 mg BID, respectively)
** A optimally tolerated dose of (IR) LYT-100 capsules, will be taken twice per day,
and not to exceed 750 mg BID. |
Part 3 Criteria for Evaluation
[0498] Fibrotic and inflammatory biomarkers. Serum biomarkers G-CSF, MIG, FGF-2, IL-4, IL-10,
lymphotoxin-α/TNF-β, leptin, IL-6, IL-1β, TNF-α, TGF-β1, MMP-9, TIMP-1, and MCP-1
are evaluated.
[0499] Bioimpedance, or water content measured via Bioelectrical impedance spectroscopy
(BIS). Multiple frequency bioelectrical impedance spectroscopy (BIS) provides accurate
relative measures of protein-rich fluid in the upper limb of patients. BIS is a noninvasive
technique that involves passing an extremely small electrical current through the
body and measuring the impedance (or resistance) to the flow of this current. The
electrical current is primarily conducted by the water containing fluids in the body.
BIS quantifies the amount of protein-rich fluid in lymphedema by comparison of the
affected and non-affected limbs.
[0500] Limb Volume (Perometry). Relative limb volume is measured by the truncated cone method
of circumferential tape measurement. Perometry is a noninvasive technique involving
a Perometer (Pero-System), which uses infrared light to scan a limb and obtain measurements
of the limb's circumference.
[0501] Tissue Dielectric Constant (MoistureMeterD). The tissue dielectric constant measures
the local tissue water content under the skin at various depths ranging from skin
to subcutis. The results are converted into a 0-100% scale to reflect subcutaneous
fluid deposition that can occur in early stage lymphedema.
[0502] Tissue Firmness (Tonometry/SkinFibroMeter). A tonometer device is pressed into the
skin to measure the amount of force required to make an indent in the tissue. The
resulting measurement gauges the degree of firmness or fibrosis (tissue scarring)
under the skin to assess the severity of lymphedema. (r) at dorsal surface of arm
10cm below the elbow.
[0503] Visual-analogue scales for pain, swelling, discomfort, and function. This graphic
scale has a straight line with endpoints from 0 to 10 that is marked by the patient
to correlate to their extreme limits of pain, swelling, discomfort and function, ranging
from "not at all" to "as bad as it could be." The higher marks on the line indicates
the worse condition.
[0504] Upper Limb Lymphedema Score 27 (ULL27) is a self-report tool consisting of 27 questions
to evaluate arm lymphedema and associated symptoms in breast cancer survivors. Responses
are given on a 5-pount Likert scale ranging from "never" to "always." Five domains
are addressed: physical (15 items), psychological (7 items) and social (5 items),
with scores ranging from 0 to 100 (100 being the best score possible). Lower scores
indicate a higher quality of life
[0505] Lymphedema Life Impact Scale (LLIS) is a comprehensive lymphedema-specific instrument
to measure impairments, activity limitations, and participation restrictions in patients
with any extremity lymphedema. It is an 18-question assessment tool that includes
physical, psychosocial, and functional domains. The Scale is designed to work in conjunction
with an impairment calculator to determine the impairment severity.
[0506] The protein-rich interstitial fluid accumulation in lymphedema leads to inflammation
and an accumulation of fibroblasts, adipocytes, and keratinocytes that transform the
initially soft swollen tissue into a hard fibrotic tissue with stiff, thickened skin.
Fibrosis is a scarring process, which is characterized by excess deposition of collageneous
and non-collagenous extracellular matrix (ECM) due to the accumulation, proliferation,
and activation of fibroblasts and myofibroblasts.
[0507] Fibroblasts are the main cells that produce, maintain, and reabsorb extracellular
matrix (ECM) (reviewed in
Kendall and Feghali-Bostwick, Front. Pharmacol., 27 May 2014). Fibroblasts produce the structural proteins of the ECM, expressing different ECMs
in different tissues requiring differing degrees of rigidity and flexibility; e.g.,
fibril rigidity is provided by collagen type I, while expansive stretching ability
is provided by elastin proteins. As the major producers of ECM, fibroblasts are also
the central mediators of the pathological fibrotic accumulation of ECM and of the
cellular proliferation and differentiation that occurs in response to prolonged tissue
injury and chronic inflammation in multiple fibrotic diseases including lymphedema.
[0508] During initiation and progression of fibrotic disease, such as lymphedema, fibroblasts
become activated by inflammatory cytokines and differentiate into myofibroblasts that
are characterized by up-regulated cellular migration and a contractile apparatus.
Myofibroblasts also display exaggerated ECM production, with increase in the relative
production of collagen type I, which stimulates increased chemical signaling secretion
and signaling responsiveness. The response is amplified, i.e., cytokines, such as
TGFβ1, provide further myofibroblast activation, promoting further collagen deposition,
and so forth.
[0509] Fibroblasts and myofibroblasts also produce adhesive proteins such as fibronectin
and laminin, which form the connection between cells and the ECM and are essential
for collagen assembly into ECM. During fibrosis, aberrant fibronectin-matrix assembly
is a major contributing factor to the switch from normal tissue repair to dysregulated
fibrosis. Although collagen is the most predominant ECM component of fibrotic tissue,
excessive deposition of fibronectin also occurs, and precedes the collagen deposition
(
To and Midwood, Fibrogenesis Tissue Repair. 2011; 4: 21, and references therein). For example, in glomerular and interstitial fibrosis, a
significantly elevated expression of total fibronectin is observed, with increased
levels of EIIIA+, EIIIB+ and oncofetal (IIICS+) isoforms detected in specific areas
of the kidney and in areas of fibrosis.
[0510] In addition to ECM deposition, fibroblasts also serve as key players of the immune
system with active roles in inflammation and immune cell recruitment (reviewed in
Linthout et al., Cardiovascular Research, Volume 102, Issue 2, 1 May 2014, Pages 258-269). On the one hand, fibroblasts drive homing of circulating leucocytes via the release
of chemokines, promote the recruitment of circulating leucocytes, and aid retention
and survival of immune cells in fibrotic tissue. On the other hand, fibroblasts are
activated by components of the innate and adaptive immunity; i.e., they are stimulated
chemically by inflammatory agents to differentiate into myofibroblasts with up-regulated
rates of matrix production. In other words, fibroblasts can contribute to chronic
inflammation, and reciprocally, inflammatory cytokines can promote fibroblast to myofibroblast
transition, facilitating fibrosis.
Example 3: LYT-100 Significantly Reduced Area of Fibrosis in Mouse Model
[0511] Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation, hepatocyte
ballooning and degeneration progressing to liver fibrosis. LYT-100 was orally administered
at 0 mL/kg (Vehicle only: 0.5% CMC) or 10 mL/kg twice daily from 6-9 weeks of age
in 18 male mice in which NASH mice was induced by a single subcutaneous injection
of 200 µg streptozotocin solution 2 days after birth and feet with a high fat diet
after 4 weeks of age. LYT-100 was administered at an oral dose of 30 mg/kg twice daily
(60 mg/kg/day). In addition, nine non-NASH mice were fed with a normal diet and monitored.
[0512] FIG. 2 depicts representative micrographs of Sirius-red stained liver sections illustrating
that LYT-100 significantly reduced the area of fibrosis. Specifically, liver sections
from the vehicle group exhibited collagen deposition in the pericentral region of
the liver lobule. And the LYT-100 group showed a significant reduction in the fibrosis
area compared to the vehicle group. These results demonstrate that LYT-100 has a potential
to inhibit the progression of fibrosis.
FIG. 3 illustrates the percent fibrosis area for LYT-100 versus vehicle and control. The
results are also summarized
Table 9 below.
Table 9: Fibrosis Area
Parameter (mean ± SD) Fibrosis Area (%) |
Normal (n=9) 0.27 ± 0.06 |
Vehicle (n=7) 1.02 ± 0.20 |
LYT-100 (n=8) 0.64 ± 0.31* |
*p<0.01, Vehicle vs LYT-100 |
[0513] Liver sections from the Vehicle group exhibited severe micro- and macro vesicular
fat deposition, hepatocellular ballooning and inflammatory cell infiltration. While
LYT-100 hepatocyte ballooning was similar to Vehicle, scores were lower for lobular
inflammation and steatosis.
(Table 10).
Table 10: NAFLD Activity Score
Group |
n |
Score |
NAS (mean ± SD) |
Steatosis |
Lobular Inflammation |
Hepatocyte ballooning |
0 |
1 |
2 |
3 |
0 |
1 |
2 |
3 |
0 |
1 |
2 |
Normal |
9 |
9 |
- |
- |
- |
9 |
- |
- |
- |
9 |
- |
- |
0.0 ± 0.0 |
Vehicle |
7 |
2 |
5 |
- |
- |
- |
2 |
1 |
4 |
- |
1 |
6 |
4.9 ± 1.2 |
LYT-100 |
8 |
4 |
3 |
1 |
- |
- |
5 |
3 |
- |
- |
- |
8 |
4.0 ± 1.1 |
Definition of NAS Components
[0514]
Item |
Score |
Extent |
Steatosis |
|
|
0 |
<5% |
1 |
5-33% |
2 |
>33%-66% |
3 |
>66% |
Hepatocyte Ballooning |
0 |
None |
1 |
Few balloon cells |
2 |
Many cells/prominent ballooning |
0 |
No foci |
Lobular Inflammation |
1 |
<2 foci/200x |
2 |
2-4 foci/200x |
3 |
>4 foci/200x |
[0515] As evidenced above, LYT-100 significantly reduced the area of fibrosis, reduced inflammation,
and reduced accumulation of fat (steatosis), as compared to the untreated NASH mice.
Example 4: LYT-100 Reduction of TGF-β-induced proliferation and collagen levels in
Primary Mouse Lung Fibroblasts
[0516] LYT-100 was evaluated for an ability to reduce the TGF-β-induced proliferation of,
and collagen levels in, Primary Mouse Lung Fibroblasts (PMLF).
[0517] Inhibition of p38 members by LYT-100 is important as p38 members are activated by
TGF-β signaling pathway. TGF-β activation, in turn plays a significant role in transcriptional
induction of the collagen type IA2. The collagen type IA2 makes up the majority of
extracellular matrix, which accumulates during progression of, e.g., IPF. Deposition
of collagen is one of the most important components of fibrotic lung tissue, a process
primarily induced by TGF-β. Since accumulation of insoluble collagen encroaches on
the alveolar space, it plays pivotal role in distortion of lung architecture and progression
of IPF. Therefore, inhibition of TGF-β -induced collagen synthesis is an important
target for IPF. In addition to insoluble (structural) collagen, fibrotic lungs of
IPF patients also show high levels of non-structural (soluble) collagen.
[0518] Although this type of collagen may eventually become insoluble collagen, until then,
soluble collagen can serve as a ligand for integrin receptors of lung fibroblasts
and epithelial cells. Binding of soluble collagen to these receptors induces proliferation
and migration of these cells. Fibronectin is another important component of fibrotic
lungs as it is induced by TGF-β and functions both as a structural component of extra
cellular matrix (ECM), as well as a ligand for integrin receptors. Just like soluble
collagen, binding of fibronectin to integrin receptors induces the proliferation of
fibroblast and epithelial cells of the lungs and plays significant role in progression
of IPF.
Preparation of Primary Mouse Lung Fibroblast
[0519] Primary Mouse lung fibroblast were prepared as follows. One lung was removed from
2 months old male BalbC Mouse, perfused with sterile PBS, minced and incubated in
2 ml of serum free Dulbecco's Modified Eagle's Medium (DMEM) containing 100 µg/ml
of collagenase I for one hour at 37°C. Each sample was centrifuged at 1500 r.p.m (revolution
per minute) for 5 minutes, washed three times with PBS and the final cellular pellet
was resuspended in DMEM supplemented with 10% serum and Pen/Strep, and incubated in
150 mm plates at 37
oC with 80% humidity and %% CO
2. The growth medium was removed and fresh medium was added every day for 10 days.
Testing the effect of LYT-100 on Survival of Primary Mouse Lung Fibroblast
[0520] LYT-100 was evaluated for an ability to alter TGF-β-induced proliferation of PMLF.
At the end of 10-day incubation period above, lung fibroblasts were confluent. Before
testing the effect of LYT-100 on survival of these cells, fibroblasts were tripsinized
and five thousand cells were plated into 96 well plate in 200 µL complete DMEM, and
incubated until cells reached to 95-100% confluency, then the medium was removed and
complete DMEM containing Prolin (10 µM) and Ascorbic acid (20 µg/ml) was added. LYT-100,
dissolved in pure ethanol, was added to the plates at a final concentration of 500
µM 1 h prior to addition of TGF-β (5ng/ml), and cells were further incubated for 72
hrs. One hundred µL of the growth medium was removed and 20 µL of MTT stock solution
(prepared in PBS at 5.5 mg/ml concentration) was added and cells were incubated for
4 hrs, then 100 µl of DMSO was added, and absorbance of developed color was monitored
at 540-690 nm.
[0521] As shown at
FIG. 4A, LYT-100 did not affect the survival of PMLF alone. TGF-β (5 ng/ml) significantly
induced the proliferation of PMLF by nearly 45% (p=0.001), and LYT-100 did appear
to diminish TGF-β-induced proliferation of PMLF by 10%, but this effect was not statistically
significant (p=0.19).
TGF-β-induced Insoluble Collagen Synthesis using 6-well plate format
[0522] The effect of LYT-100 on inhibition of TGF-β-induced collagen synthesis was evaluated
in PMLF in a 6-well format. One hundred thousand Primary Mouse Lung Fibroblasts were
plated in 6-well plates and incubated in complete DMEM until they reached confluency.
The incubation medium was removed and complete DMEM containing Prolin (10 µM) and
Ascorbic acid (20 µg/ml) was added. LYT-100 was added to the plates at a final concentration
of 500µM 1 h prior addition of TGF-β (5ng/ml), and cells were further incubated for
72 hrs.
[0523] Supernatant was removed, cells were washed with cold PBS, 1 ml Sircol reagent was
added. The Sircol reagent contains the collagen binding dye Sirius red. The cells
were scraped off with Sircol reagent and samples were shaken for 5 h at room temperature
(RT), centrifuged at 10,000 rpm for 5 min, supernatant was removed, the pellet was
washed in 0.5 M acetic acid to remove unbound dye, and recentrifuged at 10,000 rpm
for 5 min, supernatant was removed and the final pellet was dissolved in 1 ml 0.5M
NaOH and shaken at RT for 5 h. A sample of 100 µl of resultant solution was placed
in 96-well. The color reaction was assessed by optical density at a wave length of
600 nm.
[0524] As shown in
FIG. 4B, PMLF responded to TGF-β with increased total collagen levels, (increase of 21%; p=0.0087).
LYT-100 inhibited this induction by 15% (p=0.026), as compared to the TGF-β alone,
without reducing the background level of collagen.
TGF-β-induced Insoluble Collagen Synthesis using 96-well plate format
[0525] The effect of LYT-100 on TGF-β-induced collagen was confirmed in a high throughput
collagen assay using 96-well plate format. Approximately 5,000 primary mouse fibroblasts
were plated in complete DMEM in 96 well plates and incubated for 3 days at which time
the cultures achieved confluency. After cells reached confluency, the medium was removed
and fresh DMEM supplemented with ascorbic acid (20 µg /ml) and prolin (10 µMol) was
added. LYT-100 was then added to the appropriate cultures at a final incubation concentration
of 500 µM. One hour later, TGF-β was added to the appropriate cultures at a final
concentration of 5 ng/ml. After 72 hours, the media was replaced with a 0.5% glutaraldehyde
solution. After 30 minutes, the adherent cells were washed and subsequently incubated
with acetic acid at a final concentration of 0.5M. After a 30 min room temperature
incubation, and subsequent washing steps, the wells were incubated with Sircol reagent.
After 5 hours, the unbound dye was removed and the plates were washed and allowed
to dry. To extract collagen-bound Sircol, 100 µL of alkaline solution (0.5M NaOH)
was added and plates were shaken for 1 h on rotary shaker at room temperature. Absorbance
at 600 nm was determined to detect bound collagen.
[0526] As shown in
FIG. 4C, in the 6-well format, TGF-β induced insoluble collagen level by 40% (p=0.0002), LYT-100
diminished this TGF-β-stimulated collagen accumulation by 24% (p=0.0003) without reducing
the background level of collagen.
TGF-β-induced Soluble Fibronectin and Collagen Synthesis
[0527] LYT-100 was evaluated for its ability to modify TGF-β-induced soluble fibronectin
and soluble collagen synthesis using a selective ELISA. Approximately 5,000 primary
mouse lung fibroblasts were plated in complete DMEM in 96 well plates and incubated
for 3 days at which time the cultures achieved confluency. After cells reached to
confluency, medium was removed and fresh DMEM supplemented with ascorbic acid (20
µg /ml) and prolin (10 µM) was added. LYT-100 was then added to the appropriate cultures
at a final incubation concentration of 500 µM. One hour later, TGF-β (5 ng/ml) was
added to the appropriate cultures at a final concentration. After 72 hours, 200 µl
samples of the supernatant were placed onto an ELISA plate and incubated overnight.
After blocking with %1 BSA for 2 h, plates were incubated with either an anti-collagen
type I antibody or an anti-fibronectin antibody.
[0528] The plates were washed after 1 hour and incubated with secondary horseradish peroxidase-conjugated
antibodies (anti-goat for the collagen antibody, anti-rabbit for the fibronectin antibody).
After a series of washing steps the color reagent TMB (3,3',5,5'-Tetramethylbenzidine)
was added and 15 minutes later the reactions were terminated with equal volumes of
2 N H2SO4. The levels of soluble collagen and fibronectin were determined by evaluating
absorbance at 450 nm.
[0529] Referring to
FIG. 4D, TGF-β induced the level of soluble fibronectin by 16% (p=0.0021). LYT-100 inhibited
TGF-β-dependent induction of fibronectin by 11% (p=0.0185). Moreover, LYT-100 also
inhibited the background level of soluble fibronectin by 10% (p=0.03).
[0530] As shown in
FIG. 4E, TGF-β induced the level of soluble collagen by 20% (p=0.0185). LYT-100 inhibited
this TGF-β-dependent increase by 36% (p=0.0001). Moreover, it also inhibited background
level of soluble collagen by 23% (p=0.0115).
[0531] In summary, LYT-100 was found to: (i) reduce TGF-β-induced cell proliferation, (ii)
reduce both background and TGF-β-induced levels of insoluble (structural) collagen;
(iii) reduce both background and TGF-β-induced levels of soluble collagen; and (iv)
reduce both background and TGF-β-induced levels of soluble fibronectin.
[0532] During the progression of IPF, an accumulation of extra cellular matrix components
such as collagen and an increase in the fibroblast population is observed. Persistent
proliferation of fibroblasts is considered an important contributor to the lung architecture
in IPF, including the diminished interstitial spaces of the alveoli. Thus, reducing
TGF-β-induced proliferation of fibroblasts and structural collagen with LYT-100 has
the potential to prolong lung function in IPF. In addition to inhibiting TGF-β-induced
insoluble collagen level, LYT-100 also inhibits TGF-β-induced secreted collagen and
fibronectin β. Secreted collagen and fibronectin not only increase the rate of formation
of fibrotic foci in the lung, these proteins can also act as ligands for integrin
receptors. When integrin receptors are activated they induce not only the proliferation
of epithelial cells and fibroblasts of the lungs, but they also, along with TGF-β,
induce epithelial mesenchymal transition (EMT) of the epithelial cells of the lungs.
EMT causes these cells to migrate to different regions of the lungs. This migration
is considered to be a very important contributor for the generation of new fibrotic
foci in the lungs and progression of IPF.
[0533] LYT-100 has the ability to inhibit TGF-β-induced pro-fibrotic processes and to reduce
basal factors, which have the potential to exacerbate ongoing fibrosis.
Example 5: Effect of LYT-100 on L929 Cells
[0534] The effect of LYT-100 on survival of L929 Cells was determined. Five thousand L929
cells were plated in completed DMEN and incubated until confluency for 3 days. Medium
was removed and complete DMEM containg Prolin (20 µg/ml) and ascorbic acid (10 uM)
was added. LYT-100 was given at 500µM 1 h prior addition of TGFb (5ng/ml), and cells
were further incubated for 72 hrs. 100µL of medium was removed, 20µL MTT solution
was added for 4 hrs, then 100 µl of DMSO was added, and absorbance of developed dark
pink color was determined at 54-690 nM.
FIG. 5A illustrates that LYT-100 does not affect survival of L929 cells.
[0535] The effect of LYT-100 on TGF-induced collagen synthesis in 6-wells was determined.
100,000 L929 cells were plated in complete DMEN and incubated until confluency for
3 days. Medium was removed and complete DMEM containg Prolin (20 µg/ml) and ascorbic
acid (10 µM) was added. LYT-100 was given at 500µM 1 hour prior addition of TGF-(3
(5ng/ml). Cells were further incubated for 72 hrs. Supernatant was removed, cells
were washed with cold PBS, 1 ml SIRCOL reagent was added onto the cells and cells
were scraped off, samples were shaken for 5 h.at RT, centrifuged at 10.000 rpm for
5 min, supernatant was removed, pellet was dissolved in 0.5 M acetic acid to remove
unbound dye, and re-centrifuged at 10.000 rpm for 5 min, supernatant was removed and
final pelet was dissolved in 1 ml 0.5M NaOH, shaken at RT for 5 h, 100 µl of resulted
solution was placed in 96-well and O.D was determined at 600. The results are summarized
in
FIG. 5B, which illustrates that LYT-100 inhibits TGF-induced collagen synthesis. LYT-100 also
significantly inhibits collagen synthesis in the absence of added TGF-β.
[0536] Next, the effect of LYT-100 onTGF-induced collagen synthesis was confimed using 96-well
plate format. Five thousand L929 cells were plated in complete DMEN and incubated
until confluency for 3 days. Medium was removed and complete DMEM containg Prolin
(20 µg/ml) and ascorbic acid (10 µM) was added. LYT-100 was given at 500µM 1 h prior
addition of TGF-β (5ng/ml). Cells were further incubated for 72 hrs. Supernatant was
removed, 0.5% gluteraldehyde was added for 30 min at RT, removed, washed 3X with ddwater,
0.5 M acetic acid was added for 30 min at RT, removed, washed with water, air dried
and 100 µl SIRCOL dye was added for 5 h at RT. Dye was removed, plate was washed extensively
under running water, air dried and 200 µl of 0.5 M NaOH was added, plates were shaken
at RT for 1 h, and OD was determined at 600 nm. The results summarized in
FIG. 5C illustrate that LYT-100 significanly inhibited or reduced TGF-β-induced total collagen
levels. LYT-100 also signficantly inhibited or reduced total collagen level in the
absence of TGF-β induction.
[0537] The effect of LYT-100 on TGF-induced Soluble Collagen Synthesis was determined using
a 96-well plate format. Five thousand L929 cells were plated in complete DMEN and
incubated until confluency for 3 days. Medium was removed and complete DMEM containing
Prolin (20 µg/ml) and ascorbic acid (10 µM) was added. LYT-100 was given at 500µM
1 h prior addition of TGF-β (5ng/ml). Cells were further incubated for 72 hrs. 200
µl supernatant of 96-well SIRCOL plate was placed onto ELISA plate and incubated O/N.
Next day, supernatant was removed and 100 ul of 1%BSA in PBST was added and incubated
for 2 h at RT, BSA was removed, plate was washed 3x with 200 µl of PBST, and anti-collagen
type I a.b was added at 1 :2000 dilution (prepared in %1 BSA in PBST), incubated at
RT for 1 h, primary a.b was removed, plate was washed 3x with 200 µl PBST, and secondary
anti-goat HRP was added at 1:2000 dilution, incubate at RT for 1 h, removed, plate
was washed 3x with 200 µl PBST and 100 µl of TMB solution was added for color development
for 15 min, then 100 µl of 2 N H2SO4 was added to stop the reaction and O.D of developed
yellow color was determined at 450 nm.
[0538] As illustrated in
FIG. 5D, LYT-100 significantly inhibits TGF-β-induced soluble collagen levels. LYT-100 also
signficantly reduced soluble collagen levels in the absence of TGF-β-induction.
[0539] Fibronectin is another important component of fibrotic lungs as it is induced by
TGF-β and functions both as a structural component of extra cellular matrix as well
as well as a ligand for integrin receptors. Just like soluble collagen, binding of
fibronectin to integrin receptors induces the proliferation of fibroblast and epithelial
cells of the lungs. The effect of LYT-100 of TGF-induced soluble fibronectin synthesis
was determined using a process similar to that described in the above paragraph for
soluble collagen synthesis except that a fibronectin ELISA was used. As illustrated
in
FIG. 5E, LYT-100 signficantly reduced soluble fibronectin levels, in the absence and presence
of TGF-β-induction.
Example 6: LYT-100 Study in Mouse Model of Lymphedema
[0540] This experiment tests the effect of LYT-100 and LYT-101 (pirfenidone) on the mouse
tail model of lymphedema. LYT-100 and LYT-101 is delivered for 6-12 weeks via b.i.d.
oral gavage, in mice with ablated tail lymphatics via circumferential excision and
ablation of collecting lymphatic trunks. Tail volume is measured weekly for all animals,
starting pre-surgery and continuing through the 12-week interim sacrifice and 18-week
study conclusion. At sacrifice, tails are harvested for histology and immunofluorescent
imaging to characterize tissue changes with surgery and LYT-100 or LYT-101 treatment.
Tail volume and markers of lymphatics, fibrosis, and inflammation are compared between
LYT-100, LYT-101, and an active-surgery/control-drug group.
[0541] The effect of LYT-100 and LYT-101 is examined on tail volume in an experimental model
of lymphedema, as measured weekly by the truncated cone method. And the effect of
LYT-100 and LYT-101 on histological markers in an experimental model of lymphedema,
including markers of lymphatics, fibrosis, and inflammation will also be evaluated.
[0542] Animals: 66 adult females (10-14 week old) C57BL/6 J mice, fed
ad libitum in 12:12 light / temperature-controlled and pathogen-free facility. 10 animals per
group, with allowance for 1 spare per/group. Oral gavage can be performed using 1.5-in.,
curved, 20-gauge, stainless steel feeding needles with a 2.25-mm ball dipped in 1
g/mL sucrose.
[0543] Surgery: The superficial and deep collecting lymphatics of the mid portion of the tail were
excised using a 2-mm full-thickness skin and subcutaneous excision performed at a
distance of 15 mm from the base of the tail. Lymphatic trunks (collecting lymphatics)
adjacent to the lateral veins were identified and ablated through controlled, limited
cautery application under a surgical microscope.
[0544] The dosing amounts, route and schedule are provided in
Table 11.
Table 11 |
Group |
Test article |
Test article preparation |
Dosing |
Dosing route and schedule |
Group 1 |
LYT-100 |
Crystals ground into fine powder and suspended in 0.5% carboxymethycellulose (40mg/mL) |
250mg/kg/day |
Oral gavage, twice daily |
Group 2 |
LYT-101 |
Crystals ground into fine powder and suspended in 0.5% carboxymethycellulose (40mg/mL) |
250mg/kg/day |
Oral gavage, twice daily |
Group 3 |
Control |
0.5% carboxymethycellulose |
10 mL/kg/day |
Oral gavage, twice daily |
Group 4 |
LYT-100 |
Crystals ground into fine powder and suspended in 0.5% carboxymethycellulose (40mg/mL) |
250mg/kg/day |
Oral gavage, twice daily |
Group 5 |
LYT-101 |
Crystals ground into fine powder and suspended in 0.5% carboxymethycellulose (40mg/mL) |
250mg/kg/day |
Oral gavage, twice daily |
Group 6 |
Control |
0.5% carboxymethycellulose |
10 mL/kg/day |
Oral gavage, twice daily |
[0545] Measurements are provided in
Table 12.
Table 12: Measurements |
Tail volume |
Calculated with truncated cone formula (Sitzia 1995) and confirmed using histological
measurements of soft tissue thickness of the skin/subcutaneous tissues was measured
serially using digital images of histology slides stained with hematoxylin and eosin |
Histology |
Tissues fixed in 4% paraformaldehyde at 4° C., decalcified in 5% sodium EDTA (Santa
Cruz Biotechnology, Dallas, Tex.), embedded in paraffin, and sectioned at 5 micrometers.
Cut sections rehydrated and heat-mediated antigen unmasking performed using 90° C
sodium citrate (Sigma-Aldrich). Non-specific binding blocked with 2% BSA/20% animal
serum. Tissues incubated overnight with primary antibody at 4° C. Primary antibodies
used for immunohistochemical stains include goat anti-mouse LYVE-1, rat anti-mouse
CD45, rabbit anti-mouse CD4, Cy3-conjugated mouse anti-αSMA (from Sigma-Aldrich),
rabbit anti-human IFN-γ, rabbit anti-mouse TGF-β1, rabbit anti-mouse p-SMAD3, rabbit
anti-mouse collagen I (all from ABCAM, Cambridge, MA) |
Immunofluorescence imaging |
Immunofluorescence staining performed with AlexaFluor fluorophore-conjugated secondary
antibodies (Life Technologies, Norwalk, CT). Images scanned using Mirax imaging software
(Carl Zeiss). Peri-lymphatic CD45+ and CD4+ cell counts assessed by counting positively
stained cells within 50 µm of the most inflamed lymphatic vessel in each quadrant
of the leg. Positively stained cells counted by two blinded reviewers in four randomly-selected,
40× high-power fields in a minimum of 4 fields per animal. Collagen I deposition quantified
using Metamorph software (Molecular Devices, Sunnyvale, CA) in dermal areas of 5 µm
cross-sections. This analysis confirmed using picrosirius red staining (Polysciences,
Warrington, PA) using manufacturer's instructions. Scar index quantified with Metamorph
software by calculating the ratio of red-orange:green-yellow fibers with higher numbers
representing increased scarring. |
[0546] Study procedure and timing are provided in
Table 13.
Table 13: Study Details |
Time |
Procedure |
Notes |
0 weeks |
Surgery |
Lymphatic tail surgery |
6 weeks |
Begin intervention (daily oral gavage) |
|
12 weeks |
Interim sacrifice groups |
|
18 weeks |
Late sacrifice groups |
|
|
|
|
Weekly |
Tail volume measurement |
From pre-surgery |
|
Statistical Analysis |
ANOVA |
[0547] Further aspects of the invention are described in the following lettered paragraphs:
A. A method of treating edema, comprising administering to a subject in need thereof
an effective amount of deuterium-enriched pirfenidone having the structure:

or a pharmaceutically acceptable salt thereof,
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are selected from hydrogen and deuterium; and
at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9 , R10, and R11 is deuterium; and when R7, R8, R9, R10, and R11 are deuterium, then at least one of R1, R2, R3, R4, R5, and R6 is deuterium; and
wherein edema is treated in the subject.
B. The method of lettered paragraph A, wherein the deuterium-enriched pirfenidone
has the structure:

or a pharmaceutically acceptable salt thereof.
C. The method of lettered paragraph A or B, wherein the edema is lymphedema.
D. The method of lettered paragraph C, wherein the lymphedema is secondary lymphedema.
E. The method according to any of the preceding lettered paragraphs, wherein the subject
has received treatment for cancer, and the lymphedema is associated with the cancer
treatment or diagnosis.
F. The method according to any of the preceding lettered paragraphs, wherein the subject
has breast cancer-related arm lymphedema.
G. The method according to any of the preceding lettered paragraphs, wherein the subject
has mild to moderate breast cancer-related lymphedema.
H. The method according to any of the preceding lettered paragraphs, wherein the subject
is receiving or has received chemotherapy or radiation therapy.
I. The method according to any of the preceding lettered paragraphs, wherein at least
one of the positions represented as D independently has deuterium enrichment of no
less than about 95%.
J. The method according to any of the preceding lettered paragraphs, wherein at least
one of the positions represented as D independently has deuterium enrichment of no
less than about 98%.
K. The method according to any of the preceding lettered paragraphs, wherein at least
one of the positions represented as D independently has deuterium enrichment of no
less than about 99%.
L. The method according to any of the preceding lettered paragraphs wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 250 - 2500 mg.
M. The method of lettered paragraph L, wherein the deuterium-enriched pirfenidone
is administered orally at a total daily dose of 500 - 1500 mg.
N. The method of lettered paragraph M, wherein the deuterium-enriched pirfenidone
is administered orally at a total daily dose of 750 - 1000 mg.
O. The method of lettered paragraph M, wherein the deuterium-enriched pirfenidone
is administered orally twice a day at a total daily dose of 1500 mg.
P. The method of lettered paragraph M, wherein the deuterium-enriched pirfenidone
is administered orally twice a day at a total daily dose of 1000 mg.
Q. The method of lettered paragraph M, wherein the deuterium-enriched pirfenidone
is administered orally twice a day at a total daily dose of 500 mg.
R. The method of lettered paragraph M, wherein the deuterium-enriched pirfenidone
is administered orally once a day at a total daily dose of 1500 mg.
S. The method of lettered paragraph M, wherein the deuterium-enriched pirfenidone
is administered orally once a day at a total daily dose of 1000 mg.
T. The method of lettered paragraph M, wherein the deuterium-enriched pirfenidone
is administered orally once a day at a total daily dose of 750 mg.
U. The method of lettered paragraph M, wherein the deuterium-enriched pirfenidone
is administered orally once a day at a total daily dose of 500 mg.
V. The method according to any of the preceding lettered paragraphs wherein the deuterium-enriched
pirfenidone is administered with food.
W. The method according to any of the preceding lettered paragraphs wherein the deuterium-enriched
pirfenidone is administered without food.
X. The method according to any of the preceding lettered paragraphs, wherein the deuterium-enriched
pirfenidone is in tablet form.
Y. A method of treating interstitial lung disease (ILD), comprising administering
to a subject in need thereof an effective amount of deuterium-enriched pirfenidone
having the structure:

or a pharmaceutically acceptable salt thereof,
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are selected from hydrogen and deuterium; and
at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9 , R10, and R11 is deuterium; and when R7, R8, R9, R10, and R11 are deuterium, then at least one of R1, R2, R3, R4, R5, and R6 is deuterium; and
wherein ILD is treated in the subject.
Z. The method of lettered paragraph R, wherein the deuterium-enriched pirfenidone
has the structure:

or a pharmaceutically acceptable salt thereof.
AA. The method of lettered paragraph Y or Z, wherein the ILD is idiopathic pulmonary
fibrosis (IPF).
AB. The method according to any one of lettered paragraphs Y-AA, wherein at least
one of the positions represented as D independently has deuterium enrichment of no
less than about 95%.
AC. The method according to any one of lettered paragraphs Y-AB, wherein at least
one of the positions represented as D independently has deuterium enrichment of no
less than about 98%.
AD. The method according to any one of lettered paragraphs Y-AC, wherein at least
one of the positions represented as D independently has deuterium enrichment of no
less than about 99%.
AE. The method according to any one of lettered paragraphs Y-AD, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 250 - 2500 mg.
AF. The method according to any one of lettered paragraphs Y-AD, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 500 - 1500 mg.
AG. The method according to any one of lettered paragraphs Y-AD, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 750 - 1000 mg.
AH. The method according to any one of lettered paragraphs Y-AD, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 1500 mg.
AI. The method according to any one of lettered paragraphs Y-AD, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of of 1000 mg.
AJ. The method according to any one of lettered paragraphs Y-AD, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 500 mg.
AK. The method according to any one of lettered paragraphs Y-AD, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 1500 mg.
AL. The method according to any one of lettered paragraphs Y-AD, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 1000 mg.
AM. The method according to any one of lettered paragraphs Y-AD, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 750 mg.
AN. The method according to any one of lettered paragraphs Y-AD, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 500 mg.
AO. The method according to any one of lettered paragraphs Y-AN, wherein the deuterium-enriched
pirfenidone is administered with food.
AP. The method according to any one of lettered paragraphs Y-AN, wherein the deuterium-enriched
pirfenidone is administered without food.
AQ. The method according to any one of lettered paragraphs Y-AP, wherein the deuterium-enriched
pirfenidone is in tablet form.
AR. A method of treating a fibrotic or collagen infiltration disorder, comprising
administering to a subject in need thereof an effective amount of deuterium-enriched
pirfenidone having the structure:

or a pharmaceutically acceptable salt thereof,
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are selected from hydrogen and deuterium; and
at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9 , R10, and R11 is deuterium; and when R7, R8, R9, R10, and R11 are deuterium, then at least one of R1, R2, R3, R4, R5, and R6 is deuterium; and
wherein the fibrotic or collagen infiltration disorder is treated in the subject.
AS. The method of lettered paragraph X, wherein the deuterium-enriched pirfenidone
has the structure:

or a pharmaceutically acceptable salt thereof.
AT. The method according to any one of lettered paragraphs AR-AS, wherein at least
one of the positions represented as D independently has deuterium enrichment of no
less than about 95%.
AU. The method according to lettered paragraph AT, wherein at least one of the positions
represented as D independently has deuterium enrichment of no less than about 98%.
AV. The method according to lettered paragraph AU, wherein at least one of the positions
represented as D independently has deuterium enrichment of no less than about 99%.
AW. The method according to any one of lettered paragraphs AR-AV, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 250 - 2500 mg.
AX. The method according to any one of lettered paragraphs AR-AV, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 500 - 1500 mg.
AY. The method according to any one of lettered paragraphs AR-AV, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 750 - 1000 mg.
AZ. The method according to any one of lettered paragraphs AR-AV, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 1500 mg.
BA. The method according to any one of lettered paragraphs AR-AV, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 1000 mg.
BB. The method according to any one of lettered paragraphs AR-AV, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 500 mg.
BC. The method according to any one of lettered paragraphs AR-AV, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 1500 mg.
BD. The method according to any one of lettered paragraphs AR-AV, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 1000 mg.
BE. The method according to any one of lettered paragraphs AR-AV, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 750 mg.
BF. The method according to any one of lettered paragraphs AR-AV, wherein the deuterium-enriched
pirfenidone is administered orally at a total daily dose of 500 mg.
BG. The method according to any one of lettered paragraphs AR-BF, wherein the deuterium-enriched
pirfenidone is administered with food.
BH. The method according to any one of lettered paragraphs AR-BF, wherein the deuterium-enriched
pirfenidone is administered without food.
BI. The method according to any one of lettered paragraphs AR-BH, wherein the deuterium-enriched
pirfenidone is in tablet form.